Optical biomodule for detection of diseases at an early onset

ABSTRACT

An optical biomodule for detecting a disease specific biomarker(s), utilizing enhanced fluorescence emission (due to integration of a three-dimensional (3-D) protruded structure (s)) in a fluidic container/zero-mode waveguide, upon chemical binding of a disease specific biomarker(s) with its corresponding disease specific biomarker binder(s) (e.g., an aptamer(s)) is disclosed.

CROSS REFERENCE OF RELATED APPLICATIONS

The present application claims priority to: U.S. Provisional PatentApplication No. 62/497,979 entitled “BIOMODULE TO DETECT A DISEASE AT ANEARLY ONSET”, filed on Dec. 12, 2016.

The present application is a continuation-in-part (CIP) of U.S.Non-Provisional patent application Ser. No. 14/999,601 entitled “SYSTEMAND METHOD OF AMBIENT/PERVASIVE USER/HEALTHCARE EXPERIENCE”, filed onJun. 1, 2016 (which claims priority to: U.S. Provisional PatentApplication No. 62/230,249 entitled “SYSTEM AND METHOD OFAMBIENT/PERVASIVE USER/HEALTHCARE EXPERIENCE”, filed on Jun. 1, 2015).

The present application is a continuation-in-part (CIP) of U.S.Non-Provisional patent application Ser. No. 14/120,835 entitled“AUGMENTED REALITY PERSONAL ASSISTANT APPARATUS”, filed on Jul. 1, 2014(which claims priority to: U.S. Provisional Patent Application No.61/957,343 entitled “AUGMENTED REALITY PERSONAL ASSISTANT”, filed onJul. 1, 2013).

The present application is a continuation-in-part (CIP) of U.S.Non-Provisional patent application Ser. No. 13/448,378 entitled “SYSTEM& METHOD FOR MACHINE LEARNING BASED USER APPLICATION”, filed on Apr. 16,2012, wherein U.S. Non-Provisional patent application Ser. No.13/448,378 resulted in an issuance of U.S. Pat. No. 9,697,556 on Jul. 4,2017 (which claims priority to: U.S. Provisional Patent Application No.61/517,204 entitled “INTELLIGENT SOCIAL E-COMMERCE” filed on Apr. 15,2011).

Furthermore, the present application is a continuation-in-part (CIP) ofU.S. Non-Provisional patent application Ser. No. 13/663,376 entitled“OPTICAL BIOMODULE FOR DETECTION OF DISEASES”, filed on Oct. 29, 2012,wherein U.S. Non-Provisional patent application Ser. No. 13/663,376resulted in an issuance of U.S. Pat. No. 9,557,271 on Jan. 31, 2017(which claims priority to: U.S. Provisional Patent Application No.61/742,074 entitled “CHEMICAL COMPOSITION AND ITS DELIVERY FOR LOWERINGTHE RISKS OF ALZHEIMER'S, CARDIOVASCULAR AND TYPE-2 DIABETES DISEASES”,filed on Aug. 1, 2012; U.S. Provisional Patent Application No.61/631,071 entitled “CHEMICAL COMPOSITION AND ITS DELIVERY FOR LOWERINGTHE RISKS OF ALZHEIMER'S, CARDIOVASCULAR AND TYPE-2 DIABETES DISEASES”,filed on Dec. 27, 2011; and U.S. Provisional Patent Application No.61/628,060 entitled “CHEMICAL COMPOSITION AND ITS DELIVERY FOR LOWERINGTHE RISKS OF ALZHEIMER'S, CARDIOVASCULAR AND TYPE-2 DIABETES DISEASES”,filed on Oct. 24, 2011),

-   -   which is a continuation-in-part (CIP) of U.S. Non-Provisional        patent application Ser. No. 13/135,832 entitled “CHEMICAL        COMPOSITION AND ITS DELIVERY FOR LOWERING THE RISKS OF        ALZHEIMER'S, CARDIOVASCULAR AND TYPE-2 DIABETES DISEASES”, filed        on Jul. 15, 2011.        -   which is a continuation-in-part (CIP) of U.S.            Non-Provisional patent application Ser. No. 12/573,012            entitled, “NUTRITIONAL SUPPLEMENT FOR THE PREVENTION OF            CARDIOVASCULAR DISEASE, ALZHEIMER'S DISEASE, DIABETES AND            REGULATION AND REDUCTION OF BLOOD SUGAR AND INSULIN            RESISTANCE”, filed on Oct. 2, 2009, wherein U.S.            Non-Provisional patent application Ser. No. 12/573,012            resulted in an issuance of U.S. Pat. No. 8,017,147 on Sep.            13, 2011.

The entire contents of all Non-Provisional Patent Applications, allProvisional Patent Applications as listed in the previous paragraphand/or Application Data Sheet (ADS) are hereby incorporated byreference.

FIELD OF THE INVENTION

The present invention generally relates to (a) chemical compositions forlowering the risks of Alzheimer's, Cardiovascular and Diabetes diseases,(b) delivery (nanodelivery and molecular coupling) of bioactivecompounds and/or bioactive molecules and (c) disease diagnostics(molecular nanodiagnostics).

The present invention also relates to (d) a wearable augmented realitysubsystem, (e) a wearable subsystem and (f) a portable internetappliance in healthcare; when connected with ambient/always on sensors.

BACKGROUND OF THE INVENTION

One of the most intriguing discoveries is that many risk factors forCardiovascular, Type-1 Diabetes and Type-2 Diabetes diseases can be riskfactors for Alzheimer's disease (also known as Type-3 Diabetes disease).High blood cholesterol levels are important risk factors for Alzheimer'sdisease. If blood flow is restricted because of plaqueaccumulation/buildup in a human brain, less oxygen gets to a human brainand fewer waste residues leave a human brain.

Type-1 Diabetes disease can be caused by autoimmune destruction ofinsulin-producing cells in the pancreas, resulting in high blood sugar.The drugs that block effector-memory T cells can delay and/or preventType-1 Diabetes disease.

Type-2 Diabetes disease can be linked to excessive iron, diseasedpancreas and metabolic syndrome/obesity-hence macrophages in fattissues. The macrophages in fat tissues produce cytokine molecules,which can cause inflammations in the pancreas. Such inflammations in thepancreas can increase the insulin (a hormone needed to convertcarbohydrates, foods and glucose into energy needed for daily life)resistance and gradually the pancreas loses its ability to produceinsulin. Type-2 Diabetes disease is marked by high levels of bloodglucose resulting from defects in glucose production and/or glucoseinaction and/or insulin production and/or insulin inaction. Type-2Diabetes disease and obesity can be linked with cryptochrome, a protein.Cryptochrome can regulate/modulate/synchronize the biological clock andglucose level in a human body. An increased level of cryptochrome cansuppress/inhibit the production of enzymes (in the liver) for glucosegeneration during fasting (gluconeogenesis). Bioactive compounds and/orbioactive molecules that enhance the activity of calcineurin/NFAT can beeffective against Type-2 Diabetes disease, wherein the beta cells do notproduce enough insulin. Type-2 Diabetes disease is caused byinsufficient numbers of insulin-producing beta cells. But Type-2Diabetes disease not only lacks insulin, but also produces too muchglucagon. Normally, about 50% of the insulin produced by the pancreas isimmediately destroyed by the liver; but there may be a mechanism toregulate how much insulin enters the bloodstream. Insulin degradingenzyme (IDE) is a protease, an enzyme that chops proteins or peptidesinto smaller pieces. If insulin degrading enzyme is inhibited, insulincan remain in the blood stream longer. Insulin is involved in asurprisingly wide range of important processes, including memory andcognition—thus insulin degrading enzyme inhibitors may have multipletherapeutic applications. Insulin degrading enzyme is a thiol-sensitivezinc-metallopeptidase.

Both Type-1 and Type-2 Diabetes diseases can lead to seriouscomplications (e.g., high blood pressure, kidney disease and prematuredeath). But people with Type-1 and Type-2 Diabetes diseases cancontrol/manage the diseases to lower the risks of serious complications.

The risk of Alzheimer's disease can be linked with obesity and Type-2Diabetes disease. SorCS1 transport protein can control how the insulinreceptor moves around a cell/neuron. Deficiency in SorCS1 transportprotein can increase the risk of developing Alzheimer's disease, becauseamyloid precursor protein (APP) spends too much time in the region ofthe neuron wherein amyloid precursor protein is broken down into amyloidbeta (Aβ) protein. A human brain has a low antioxidant level andrequires a large volume of blood pumped through it to function properly.The biochemical reaction of glucose (in blood) with proteins is known asglycation. Glycation can cause problems in a human brain. The glucosemolecule can be split up/divided open by enzymes for energy consumptionin a human brain and two (2) reactive aldehydes can crosslink withproteins in a human brain—thus leading to a decreased blood flow.Another possible link is leptin, a hormone. Leptin is released by fatcells in a human body and acts on the leptin receptors in a human brainto regulate hunger. There are a number of leptin receptors all over ahuman body including in the hypothalamus of a human brain. Higher levelsof leptin can suppress appetite and enhance metabolism. Leptin alsoplays a key role in modulating insulin. But obesity can create leptinresistance—thus leptin is not transported efficiently in a human brain.Higher levels of leptin in a human brain may lower the risk ofdeveloping Alzheimer's disease. Leptin can also reduce the production ofamyloid beta protein; wherein amyloid beta protein is involved inAlzheimer's disease. Although obesity is often associated with insulinresistance and Diabetes disease, this is not always the case. However,when T-bet protein is absent, the relationship between fat and insulinresistance can be altered. T-bet is a protein that regulates thedifferentiation and function of immune cells.

Clinical and epidemiological studies have found that Type-2 Diabetesdisease and hyperinsulinaemia increased the risk of developingAlzheimer's disease. The link between hyperinsulinaemia and Alzheimer'sdisease may be insulin degrading enzyme. This enzyme degrades bothinsulin and amylin peptides related to the pathology of Type-2 Diabetesdisease along with amyloid-beta peptide, a short peptide found in excessin the Alzheimer's brain.

SUMMARY OF THE INVENTION

Chemical Compositions

The present invention relates to chemical compositions (variousembodiments) of bioactive compounds for lowering the risks ofAlzheimer's, Cardiovascular and Diabetes diseases.

Furthermore, the present invention relates to a chemical composition ofa sugar free sweetener for people with Type-2 Diabetes disease.

Furthermore, the present invention relates to various chemicalcompositions (various embodiments) of a sugar free super-sweetener forpeople with Type-2 Diabetes disease.

Passive Delivery

The present invention relates to passive delivery (various embodiments)of bioactive compounds and/or bioactive molecules.

Active Delivery

The present invention relates to active delivery (various embodiments)of bioactive compounds and/or bioactive molecules.

Nanodelivery/Molecular Coupling

The present invention relates to targeted nanodelivery and molecularcoupling (various embodiments) of bioactive compounds and/or bioactivemolecules.

Diagnostics

The present invention relates to a photonic crystal cavity basedintegrated optical diagnostic biomodule to detect a disease specificbiomarker/an array of disease specific biomarkers.

Furthermore, the present invention relates to various fluid containerbased integrated optical diagnostic biomodule(s) to detect a diseasespecific biomarker/an array of disease specific biomarkers.

Furthermore, the present invention relates to various field effecttransistor (FET) based integrated electrical diagnostic biomodule(s) todetect a disease specific biomarker/an array of disease specificbiomarkers.

Furthermore, the present invention relates to a nanohole based singlemolecule DNA/RNA sequencing electrical diagnostic biomodule to detect adisease specific biomarker/an array of disease specific biomarkers.

Furthermore, the present invention relates to an x-ray fluorescencediagnostic biomodule for detection of a disease specific biomarker/anarray of disease specific biomarkers.

Furthermore, the present invention relates to a retinal contact lenssubsystem to detect a disease specific biomarker/an array of diseasespecific biomarkers.

Furthermore, the present invention relates to a plasmonic interferometerbased integrated optical diagnostic biomodule to detect a diseasespecific biomarker/an array of disease specific biomarkers.

Integrated Diagnostics-Delivery System

The present invention relates to an integrated bioelectronics subsystemto detect a disease specific biomarker/an array of disease specificbiomarkers and actively deliver bioactive compounds and/or bioactivemolecules.

Furthermore, the present invention relates to a retinal contact lenssubsystem to deliver bioactive compounds and/or bioactive molecules.

Lab-On-Chip (LOC) Diagnostics

The present invention relates to various Lab-on-Chip subsystems andtheir applications in personalized healthcare.

Wearable Augmented Reality Subsystem with Connected Ambient/Always onSensors

The present invention relates to a wearable augmented reality subsystemwith connected ambient/always on sensors and its applications inpersonalized healthcare.

Wearable Personal Assistant Subsystem with Connected Ambient/Always onSensors

The present invention relates to a wearable subsystem with connectedambient/always on sensors and its applications in personalizedhealthcare.

Portable Internet Appliance with Connected Ambient/Always on Sensors

The present invention relates to a portable internet appliance withconnected ambient/always on sensors and its applications in personalizedhealthcare.

BRIEF DESCRIPTION OF THE TABLES

The present invention is better understood upon consideration of thedescription in conjunction with the following Tables and Figures.

Table-1A and Table-1B, wherein each table illustrates a composition of amixture of micronutrients. Table-1C illustrates a composition of amixture of micronutrients for topical use. Table-1D, Table-1E, Table-1F,Table-1G, Table-1H, Table-1I, Table-1J and Table-1K, wherein each tableillustrates a composition of a mixture of micronutrients.

Table-2A and Table-2B, wherein each table illustrates a composition of amixture of antioxidants.

Table-3A illustrates a composition of a multi-serve antioxidant liquid.Table-3B and Table-3C, wherein each table illustrates a composition of asingle-serve antioxidant liquid. Table-3D illustrates a composition of amixture of botanicals. Table-3E illustrates a composition of a mixtureof electrolytes and dextrose.

Table-4 illustrates a composition of a biodegradable plastic material.

Table-5 illustrates a composition of a mixture for expression ofbeneficial NrF₂ protein.

Table-6 illustrates molecular docking score with the mammalian Target ofRapamycin (mTOR), utilizing computational chemistry software.

Table-7A, Table-7B, Table-7C and Table-7D, wherein each tableillustrates a composition of a mixture for suppressing/inhibiting themammalian Target of Rapamycin.

Table-8A, Table-8B, Table-8C, Table-8D and Table-8E, wherein each tableillustrates a composition of a mixture for lowering the risk ofAlzheimer's disease.

Table-9 illustrates a composition of a mixture for lowering the risks ofCardiovascular disease.

Table-10A, Table-10B, Table-10C and Table-10D, wherein each tableillustrates a composition of a mixture for lowering the risk of Type-2Diabetes disease.

Table-11 illustrates a composition of a mixture of sugar-free sweetenerfor people with Type-2 Diabetes disease.

Table-12A, Table-12B, Table-12C, Table-12D, Table-12E, Table-12F,Table-12G, Table-12H, Table-12I, Table-12J, Table-12K, Table-12L andTable-12M, wherein each table illustrates a composition of a mixture ofsugar-free super-sweetener for people with Type-2 Diabetes disease.

Table-13A, Table-13B, Table-13C, Table-13D, Table-13E, Table-13F,Table-13G, Table-13H, Table-13I, Table-13J, Table-13K, Table-13L,Table-13M, Table-13N, Table-13O, Table-13P, Table-13Q, Table-13R,Table-13S, Table-13T, Table-13U, Table-13V and Table-13W, wherein eachtable illustrates a composition of a mixture of chewable/soluble stripfor health.

Table-13X illustrates a composition of probiotics. Table-13Y illustratesa composition of chemicals and minerals to protect against aging.Table-13Z1 illustrates another composition of chemicals and minerals toprotect against aging. Table-13Z2 illustrates another composition ofchemicals to protect against aging. Table-13Z3 illustrates anothercomposition of chemicals to protect against aging. Table-13Z4illustrates another composition of chemicals to protect against aging.

Table-14A illustrates various compositions of a biodegradable scaffold.Table-14B illustrates various compositions of a biodegradable scaffold,integrated with various nanowire field effect transistors.

Table-15 illustrates a composition of a biodegradable plastic material.

Table-16A illustrates various compositions for a nanostructured mesh.Table-16B illustrates various compositions for a nanostructured mesh,integrated with various nanowire field effect transistors.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 illustrates graphical interactions of Alzheimer's disease relatedgenes/proteins with a set of bioactive compounds (e.g., an antioxidant,enzymatic antioxidant, enzyme, micronutrient (mineral/vitamin) and drug)and/or bioactive molecules (e.g., enzyme molecule, protein molecule,small molecule, therapeutic molecule, DNA, gene, ribozyme, RNA,messenger RNA (mRNA), micro RNA (miRNA), Piwi-interacting RNA (piRNA)and small interfering RNA (siRNA)), according to comprehensivebiological pathway analysis (BPA) software. FIG. 1A illustrates asection of FIG. 1 and FIG. 1B illustrates a section of FIG. 1, whereinboth sections are separated by a dotted line.

FIG. 2 illustrates graphical interactions of Alzheimer's, Dementia andParkinson's disease related genes/proteins with a set of bioactivecompounds and/or bioactive molecules, according to comprehensivebiological pathway analysis software. FIG. 2A illustrates a section ofFIG. 2 and FIG. 2B illustrates a section of FIG. 2, wherein bothsections are separated by a dotted line.

FIG. 3 illustrates graphical interactions of Alzheimer's, Dementia andParkinson's disease related genes/proteins with a set of bioactivecompounds and/or bioactive molecules, according to comprehensivebiological pathway analysis software. FIG. 3A illustrates a section ofFIG. 3 and FIG. 3B illustrates a section of FIG. 3, wherein bothsections are separated by a dotted line.

FIG. 4 illustrates graphical interactions of Type-2 Diabetes diseaserelated genes/proteins with a set of bioactive compounds and/orbioactive molecules, according to comprehensive biological pathwayanalysis software. FIG. 4A illustrates a section of FIG. 4 and FIG. 4Billustrates a section of FIG. 4, wherein both sections are separated bya dotted line.

FIGS. 5A and 5B illustrate molecular docking score with the mammalianTarget of Rapamycin, according to comprehensive molecular dockinganalysis software.

FIGS. 6A, 6B, 6C, 6D and 6E illustrate targeted delivery of bioactivecompounds and/or bioactive molecules, utilizing a nanocarrier and/or ananoshell.

FIGS. 7A, 7B, 7C, 7D, 7E, 7F, 7G, 7H, 7I, 7J, 7K, 7L and 7M illustrate apassive (via a micropatch) delivery of bioactive compounds and/orbioactive molecules, utilizing thin-films, nanocrystals andmicroelectro-mechanical-system (MEMS) reservoirs. FIG. 7N illustrates aprogrammable/active (via a micropatch and microelectro-mechanical-systemreservoir(s) integrated with needles) delivery of bioactive compoundsand/or bioactive molecules, utilizing thin-films, nanocrystals,hydrogel, microelectro-mechanical-system reservoirs and micropumps. FIG.7O illustrates a programmable/active (via a micropatch andmicroelectro-mechanical-system reservoir(s) integrated with nanotubes)delivery of bioactive compounds and/or bioactive molecules, utilizingthin-films, nanocrystals, hydrogel, microelectro-mechanical-systemreservoirs and micropumps.

FIG. 8 illustrates a programmable/active (via a micropatch andmicroelectro-mechanical-system reservoir(s) integrated with needles)delivery of bioactive compounds and/or bioactive molecules, utilizing amicroelectro-mechanical-system reservoir and a micropump.

FIGS. 9A, 9B, 9C and 9D illustrate an array of photonic crystal cavitiesbased integrated optical diagnostic biomodule to detect a diseasespecific biomarker/an array of disease specific biomarkers.

FIGS. 10A, 10B, 10C and 10D illustrate (an array of fluid containersbased) integrated optical diagnostic biomodules (various embodiments) todetect a disease specific biomarker/an array of disease specificbiomarkers.

FIGS. 11A, 11B, 11C and 11D (an array of fluid containers based)illustrate integrated optical diagnostic biomodules (various otherembodiments) to detect a disease specific biomarker/an array of diseasespecific biomarkers.

FIGS. 12A, 12B and 12C illustrate (an array of fluid containers based)illustrate integrated optical diagnostic biomodules (various otherembodiments) to detect a disease specific biomarker/an array of diseasespecific biomarkers. FIGS. 12D, 12E, 12F and 12G illustrate (an array ofmicrocapillaries based) integrated optical diagnostic biomodules(various other embodiments) to detect up to two (2) million or moredisease specific biomarkers.

FIGS. 12H-12O illustrate eight embodiments of a three-dimensional (3-D)protruded optical nanoantenna.

FIGS. 12P1-12P3 illustrate three fabrication/construction methods forpatterning dimension at or less than 25 nanometers.

FIGS. 12Q1-12Q6 illustrate six fabrication/construction methods forpositioning a fluorophore (coupled with a biomarker binder) at aspecified position on a substrate

FIG. 12R1 illustrates an aptamer sensor.

FIG. 12R2 illustrates a molecular beacon.

FIG. 12R3 illustrates chemically coupled three distinct biomarker binder(e.g., an antibody/synthetically designed antibody/aptamer) A, B and C,wherein the distinct biomarker binder B and the distinct biomarkerbinder C are then chemically coupled with a plus ligation arm of shortsequences of a biological material (e.g., oligonucleotides) and a minusligation arm of short sequences of a biological material (e.g.,oligonucleotides) respectively. Thus, generating a randomly coiledsingle stranded structure composed of hundreds of copies of a biologicalmaterial, relying on proximity extension array (PEA) method and thus,subsequently leading to covalently hybridization of fluorescent orenzyme-labeled biological material.

FIGS. 12S1-12S7 illustrates seven examples of positioning a biomarkerbinder/fluorophore at a specified position with respect to athree-dimensional protruded structure.

FIG. 12T1 illustrates an open enclosure for a three-dimensionalprotruded optical nanoantenna.

FIG. 12T2 illustrates a closed enclosure for a three-dimensionalprotruded optical nanoantenna.

FIG. 12U1 illustrates a hyperbolic metamaterial surface.

FIG. 12U2 illustrates gratings for a hyperbolic metamaterial surface.

FIG. 12V illustrates an embodiment of an optical diagnostic biomodule,utilizing a one-dimensional (1-D)/two-dimensional (2-D) array of fluidiccontainers, incorporating various embodiments of three-dimensionalprotruded structures.

FIGS. 12W1-12W6 illustrate six (example) embodiments of the array offluidic containers, incorporating various embodiments ofthree-dimensional protruded structures.

FIG. 12X1 illustrates an embodiment of an optical diagnostic biomodule,utilizing a one-dimensional/two-dimensional of zero-mode waveguides,incorporating various embodiments of three-dimensional protrudedstructures.

FIGS. 12X2-12X9 illustrate five embodiments of the zero-mode waveguides,incorporating various three-dimensional protruded structures.

FIG. 12X10 illustrates a fabrication/construction method for patterningan array of zero-mode waveguides/nanoholes

FIG. 12Y illustrates an embodiment of an optical diagnostic biomodule,utilizing a one-dimensional/two-dimensional array of fluidiccontainers/zero-mode waveguides, wherein each fluidiccontainer/zero-mode waveguide can include a sharp tip (a sharp tip ofvarious configurations).

FIG. 12Z1 illustrates a light source/tunable light source in the visiblespectrum, utilizing a two-dimensional (e.g., graphene) material.

FIG. 12Z2 illustrates a light source/tunable light source in the visiblespectrum, utilizing a two-dimensional material, wherein atwo-dimensional material is functionalized with a biomarker binder.

FIG. 12Z3 illustrates a nano optical fiber.

FIGS. 13A, 13B and 13C illustrate (a two-dimensional crystal based fieldeffect transistor based integrated electrical diagnostic biomodules(various embodiments) to detect a disease specific biomarker/an array ofdisease specific biomarkers. FIG. 13D illustrates chitosan/melanin basedproton field effect transistor (H⁺ FET) integrated with a lipid layerand a nanotransmitter to detect a disease specific biomarker/an array ofdisease specific biomarkers. FIG. 13E illustrates a silicon nanowirebased field effect transistor integrated with a lipid layer and ananotransmitter to detect a disease specific biomarker/an array ofdisease specific biomarkers.

FIGS. 14A and 14B illustrate a nanohole based single molecule DNA/RNAsequencing electrical diagnostic biomodule to detect a disease specificbiomarker/an array of disease specific biomarkers (by measuring analteration/elimination of a single molecule of a single strandedDNA/RNA).

FIGS. 14C-14G illustrate a nanohole based single molecule DNA/RNAsequencing optical diagnostic biomodule.

FIG. 14H illustrates Raman shift spectrum of nucleotides A, C, G and Tof the DNA respectively.

FIGS. 14I-14J illustrate another embodiment of a nanohole based singlemolecule DNA/RNA sequencing optical diagnostic biomodule.

FIGS. 14K-14L illustrate two microfluidic waveguide configurations toseparate (blood) plasma from blood.

FIG. 14M illustrates a portable diagnostic device, which can be coupledwith a portable internet appliance (e.g., an iPhone).

FIG. 14N illustrates an example application (“App”) related to consumerhealthcare.

FIG. 15A illustrates integrated bioelectronics subsystems (variousembodiments) to detect a disease specific biomarker/an array of diseasespecific biomarkers and deliver (programmable/active) bioactivecompounds and/or bioactive molecules. FIG. 15B illustrates a nearreal-time/real-time application of the wearable integratedbioelectronics subsystem.

FIG. 16A illustrates a retinal contact lens subsystem to detect adisease specific biomarker/an array of disease specific biomarkers anddeliver (programmable/active) bioactive compounds and/or bioactivemolecules. FIG. 16B illustrates a near real-time/real-time applicationof the wearable retinal contact lens subsystem in FIG. 16A.

FIGS. 17A, 17B, 17C and 17D illustrate a near real-time/real-timewearable bioelectronics subsystem, as an augmented reality personalassistant to eavesdrop on a user's communication and anonymouslyrecommend a solution to the user. FIG. 17E illustrates interactions of anear real-time/real-time wearable bioelectronics subsystem, as anaugmented reality personal assistant with another nearreal-time/real-time wearable bioelectronics subsystem, as an augmentedreality personal assistant and a portable internet appliance via a cloudbased data storage unit.

FIG. 18A illustrates a display configuration of the portable internetappliance. FIG. 18B illustrates how the portable internet appliance canbe morphed into a small form factor. FIG. 18C illustrates how theportable internet appliance can be connected with a standalone wearabledevice. FIG. 18D illustrates a block diagram of a LifeSoC for theLifepatch. FIG. 18E illustrates how nano I/Os (e.g., sensors on orwithin a human body), nanorouters and objects can connect/communicatewith other nanoI/Os, nanorouters and objects in a ubiquitous/pervasivemanner with the internet. FIG. 18F illustrates a nanoI/O and ananorouter. FIGS. 18G and 18H illustrate various configurations of anobject.

FIGS. 19A, 19B, 19C, 19D, 19E, 19F, 19G, 19H, 19I and 19J illustratevarious (block diagram) embodiments of a photonics-lab-on chip (P-LOC).FIG. 19K illustrates a specific embodiment of Bose-Einstein condensate(BCE) based ultrafast optical switch for applications in biology. FIGS.19L, 19M and 19N illustrate an integrated device to obtain various RNAsand proteins within exosomes from a human body's blood. FIG. 19Oillustrates a nanoscope for detecting various RNAs and proteins withinexosomes from a human body's blood. FIG. 19P illustrates an array ofnanoscopes for detecting various RNAs and proteins within exosomes froma human body's blood. FIG. 19Q illustrates a plasmonic interferometerfor detecting various RNAs and proteins within exosomes from a humanbody's blood. FIG. 19R illustrates an optical assembly of plasmonicinterferometer-optical fiber-optical switch-spectrophotometer to measurethe interference patterns generated by an array of plasmonicinterferometers.

FIG. 20 illustrates an insertable photonics-lab-on-chip into theportable internet appliance. FIG. 20 also illustrates interactions witha hologram, utilizing the portable internet appliance.

FIG. 21 illustrates realization of one integrated user identificationmerging a cell phone number and e-mail identification.

FIG. 22A illustrates a sender's portable internet appliance with arecipient's portable internet appliance via a cloud based server.

FIG. 22B illustrates a sender's portable internet cloud appliance with arecipient's portable internet cloud appliance via a cloud based server.

FIG. 23 illustrates a near real-time/real-time focal point convergenceof various applications or functions with one integrated useridentification.

FIG. 24 illustrates patterns of various applications or functions of asingle user with a user-centric personal web.

FIG. 25 illustrates a social graph of a user.

FIG. 26 illustrates a flow chart method of linking of many users,utilizing machine transformations.

FIG. 27 illustrates patterns of various applications or functions ofmany users and analysis of such patterns by a cloud based machinelearning/deep learning neural networks based learning/relearninginteractive expert cognitive computer.

FIG. 28 illustrates a composite social graph of many users.

FIG. 29 illustrates a flow chart method of extracting intelligence andprediction from the collective data patterns, utilizing machinetransformations.

DETAIL DESCRIPTION OF THE INVENTION

Bioactive Compounds &/or Bioactive Molecules Interactions withGenes/Proteins

FIG. 1 illustrates direct and indirect graphical interactions ofAlzheimer's disease related genes/proteins (e.g., APOE, APP, BACE1, CLU,MAPT/TAU, PSEN1, PSEN2, SORL1, TOMM40 and UBQLN1) with a set ofbioactive compounds and/or bioactive molecules, utilizing comprehensivebiological pathway analysis software. FIG. 1A illustrates a section ofFIG. 1 and FIG. 1B illustrates a section of FIG. 1, wherein bothsections are separated by a dotted line.

FIG. 2 illustrates direct and indirect graphical interactions ofAlzheimer's, Dementia and Parkinson's disease related genes/proteins(e.g., DOPAMINE, LRRK2, MAOB, PARK2 and SNCA) with a set of bioactivecompounds and/or bioactive molecules, utilizing comprehensive biologicalpathway analysis software. FIG. 2A illustrates a section of FIG. 2 andFIG. 2B illustrates a section of FIG. 2, wherein both sections areseparated by a dotted line. FIG. 3 illustrates direct and indirectgraphical interactions of Alzheimer's, Dementia and Parkinson's diseaserelated genes/proteins (e.g., DOPAMINE, LRRK2, MAOB, PARK2 and SNCA)with a set of bioactive compounds and/or bioactive molecules, utilizingcomprehensive biological pathway analysis software. FIG. 3A illustratesa section of FIG. 3 and FIG. 3B illustrates a section of FIG. 3, whereinboth sections are separated by a dotted line.

FIG. 4 illustrates direct and indirect graphical interactions of Type-2Diabetes disease related genes/proteins (e.g., ABCC8, GCK, HNF4A, INS,INSR, KCNJ11, LPL, PPARG and SLC2A2) with a set of bioactive compoundsand/or bioactive molecules, utilizing comprehensive biological pathwayanalysis software. FIG. 4A illustrates a section of FIG. 4 and FIG. 4Billustrates a section of FIG. 4, wherein both sections are separated bya dotted line.

Furthermore, Alzheimer's disease related gene/protein APOE is linkedwith Type-2 Diabetes disease related gene/protein HNF4A.

FIGS. 1A, 1B, 2A, 2B, 3A and 3B are critical to design compositions forlowering the risks of Alzheimer's disease.

FIGS. 4A and 4B are critical to design compositions for lowering therisks of Diabetes disease.

FIGS. 5A and 5B are critical to design compositions forsuppressing/inhibiting the mammalian Target of Rapamycin.

Compositions

Compositions as described in the Tables below can module (a) geneexpression, (b) epigenetic effects and (c) genomic stability.

TABLE 1A Composition Of A Mixture Of Micronutrients - May Also IncludeSome Bioactive Compounds From Tables After This Table Unit +/−50% WT %Chemicals Pterostilbene (Nanoformulated)^(1,2) Mg 200 4.89% Resveratrol(Nanoformulated)^(1,2) Mg 200 4.89% Minerals Chromium Picolinate Mg 0.50.01% Magnesium L-Threonate Mg 400 9.78% Selenium (Selenomethionine) Mg0.1 0.00% Zinc (L-Opti) Mg 15 0.37% Vanadium Mg 0.01 0.00% NucleotidesNucleotides (DNA) Mg 400 9.78% Nucleotides (RNA) Mg 40 0.98% VitaminsVitamin B₁ (Thiamine) Mg 10 0.24% Vitamin B₃ (Nicotinamide) Mg 400 9.78%Vitamin B₅ Mg 200 4.89% Vitamin B₆ (Pyritinol Or Pyridoxal Mg 20 0.49%5'-Phosphate) Vitamin B₉ (Folate) Mg 0.5 0.01% Vitamin B₁₂(Methylcobalamin) Mg 1 0.02% Vitamin C Mg 200 4.89% Vitamin D₃(Cholecalciferol) Mg 0.25 0.01% Vitamin K₂ Mg 2 0.05% Other LactoferrinMg 2000 48.91% Total Weight G 4.09 100.00%

Mixture of micronutrients contains about 35 billion cumulative (or eachlive probiotic bacterial component at 2.5 billion CFU) CFU of:Lactobacillus acidophilus, Bifidobacterium lacti, Lactobacillusplantarum, Lactobacillus rhamnosus, Lactobacillus casei, Lactobacillussalivarius, Lactobacillus bulgaricus, Bifidobacterium breve,Lactobacillus paracasei, Lactococcus lactis, Streptococcus thermophilus,Lactobacillus brevis, Bifidobacterium bifidum and Bifidobacterium longumcan be added with composition in Table-1A.

Furthermore, live probiotic bacterial components can be encapsulatedwithin a microparticulate system (e.g., chitosan-coated alginatemicroparticulate system).

TABLE 1B Composition Of A Mixture Of Micronutrients - May Also IncludeSome Bioactive Compounds From Tables After This Table Unit +/−50% WT %Botanicals Bacopa monnieri ⁺ Mg 200 1.28% Emblica officinalis ⁺ Mg 2001.28% Vaccinium macrocarpon ⁺ Mg 800 5.12% Withania somnifera ⁺ Mg 2001.28% Chemicals Acetyl-L-Carnitine Mg 200 1.28% Alpha-R-Lipoic Acid Mg20 0.13% Beta carotene Mg 20 0.13% Chlorogenic Acid Mg 200 1.28%Citicoline (Or L-Alpha Mg 600 3.84% Glycerylphosphorylcholine) CoenzymeQ₁₀ (Nanoformulated)^(1,2) Mg 1000 6.40% Curcumin(Nanoformulated)^(1,2,3,4) Mg 200 1.28% D-Ribose Mg 400 2.56%Epigallocatechin Gallate Mg 200 1.28% L-Arginine Mg 4000 25.62%L-Glutathione (Or Ebselen Or N-Acetyl-L- Mg 200 1.28% Cysteine)L-Theanine Mg 400 2.56% Lutein Mg 10 0.06% Phosphatidylserine Mg 2001.28% Pterostilbene (Nanoformulated)^(1,2) Mg 200 1.28% PyrroloquinolineQuinone (PQQ) Mg 20 0.13% (Nanoformulated)^(1,2) Resveratrol(Nanoformulated)^(1,2) Mg 200 1.28% Touchi Mg 200 1.28% Trehalose Mg 2001.28% Ubiquinol (Nanoformulated)^(1,2) Mg 400 2.56% Zeaxanthin Mg 20.01% Minerals Chromium Picolinate Mg 0.5 0.00% Magnesium L-Threonate Mg400 2.56% Melatonin (Extended Release) Mg 3 0.02% Omega 3-6-9 Acid(Including Mg 400 2.56% Decosahexanoic Acid) (Nanoformulated)¹ PotassiumMg 400 2.56% Selenium (Selenomethionine) Mg 0.1 0.00% Zinc (L-Opti) Mg15 0.10% Zinc Sulfate Mg 250 1.60% Vanadium Mg 0.01 0.00% NucleotidesNucleotides (DNA) Mg 400 2.56% Nucleotides (RNA) Mg 40 0.26% VitaminsVitamin B₁ (Thiamine) Mg 10 0.06% Vitamin B₃ (Nicotinamide) Mg 400 2.56%Vitamin B₅ Mg 200 1.28% Vitamin B₆ (Pyritinol Or Pyridoxal Mg 20 0.13%5'-Phosphate) Vitamin B₉ (Folate) Mg 0.5 0.00% Vitamin B₁₂(Methylcobalamin) Mg 1 0.01% Vitamin C Mg 500 3.20% Vitamin D₃(Cholecalciferol) Mg 0.25 0.00% Vitamin E IU 400 1.71% Vitamin K₂ Mg 20.01% Other Lactoferrin Mg 2000 12.81% Live Lactobacillus plantarum 299vBillion 10 0.00% Total Weight G 15.61 100.00%

800 mg of L-Tryptophan can be added with composition in Table-1B.

200 mg of passion fruit tea extract can be added with composition inTable-1B.

TABLE 1C Composition Of A Mixture Of Micronutrients For Topical Use -May Also Include Some Bioactive Compounds From Tables Before & AfterThis Table Unit +/−50% WT % Botanicals Camellia sinensis (Green Tea)Extract Mg 200 4.87% Daucus carota Extract Mg 200 4.87% Emblicaofficinalis Extract Mg 200 4.87% Hippophae rhamnoides Oil Mg 200 4.87%Macrocystis pyrifera Extract Mg 200 4.87% Prunus amygdalus dulcis Mg 2004.87% (Sweet Almond) Oil Solanum lycopersicum Mg 200 4.87% ChemicalsAcetyl Hexapeptide Mg 200 4.87% Arbutin Mg 200 4.87% Caffeine Mg 200.49% Elastatropin Mg 200 4.87% Haloxyl Mg 200 4.87% Hyaluronic Acid Mg200 4.87% Hydroxytyrosol Mg 200 4.87% Hydrolyzed Wheat Protein Mg 2004.87% Palmitoyl Pentapeptide-4 Mg 200 4.87% Quercetin(Nanoformulated)^(1,2) Mg 200 4.87% Resveratrol (Nanoformulated)^(1,2)Mg 200 4.87% Superoxide Dismutase Mg 200 4.87% (Nanoformulated)^(1,2)Vitamins Pyrroloquinoline Quinone Mg 20 0.49% (Nanoformulated)^(1,2)Vitamin B₅ Mg 200 4.87% Vitamin E IU 400 6.49% Total Weight G 4.11100.00%

About 200 mg of Argan oil or about 200 mg of Coconut (preferably maturecoconut) oil or about 200 mg of Marula oil or about 200 mg Pomegranate(Punica granatum) seed oil or about 200 mg of Red Raspberry seed oil orabout 600 mg of Turmeric oil or 600 mg of Winter Rose oil can be addedwith the topical composition (formulation) in Table-1C. About 200 mg ofAloe vera extract or about 200 mg of Glycyrrhiza glabra extract or about200 mg of pine bark extract can be added with the topical composition(formulation) in Table-1C. About 100 mg of caviar extract or about 200mg of silk fibroin can be added with the topical composition(formulation) in Table-1C.

About 200 mg of extract of stem cells of leaves of Lycopersiconesculentum or about 200 mg of extract of stem cells of Malus domesticacan be added with the topical composition (formulation) in Table-1C.Furthermore, about 50 mg of a bioactive compound(s) based on naturallyoccurring antifreeze glycoproteins in Antarctic fish can be added withthe topical composition (formulation) in Table-1C

Regulatory proteins, called growth factors are biologically activemolecules. Suitable amounts of growth factors (from stem cells) can beadded. These growth factors can also be nanoformulated/nanoencapsulated(for repairing damaged skin). Fibroblasts are a type of cell found inthe connective tissue, where fibroblasts produce proteins such ascollagen, elastin and GAG, which are all critical to repairing skindensity and the overall look/quality of the skin. Suitable amounts offibroblasts can be added with the topical composition (formulation) inTable-1C.

Furthermore, activators of fibroblasts such as 1,3 beta glucan,chlorella, EGF, GHK-copper peptides, niacinamide, R-lipoic acid andretinaldehyde and/or the synergistic combination(s) of the aboveactivators of fibroblasts can activate fibroblasts and supply nutrientsto fibroblasts. Suitable amounts of activators of fibroblasts can beadded with the topical composition (formulation) in Table-1C.Furthermore, the above activators of fibroblasts can benanoformulated/nanoencapsulated. Fibroblast growth factors are criticalfor repairing damaged skin. Fibroblast growth factors can induceexpression of Nrf2, which regulates the expression of proteins involvedin the detoxification of reactive oxygen species (ROS). Suitable amountsof fibroblast growth factors can be also added with the topicalcomposition (formulation) in Table-1C.

About 0.5% by weight of ebselen, a broad-spectrum antioxidant can beadded with the topical composition (formulation) in Table-1C. Thechemical structure of ebselen is given below.

A suitable amount of selenohydantoin, an antioxidant and anticancercompound can be added with the topical composition (formulation) inTable-1C. Furthermore, a chemical derivative/structural analogue ofselenohydantoin can also be utilized. The chemical structure ofselenohydantoin is given below.

Zinc finger technology (ZFT) can be utilized to repair DNA damage andassist in the production of proteins and antioxidants within skin cells.A suitable amount of zinc finger technology can be added with thetopical composition (formulation) in Table-1C.

Additionally, a nanoemulsion system/biodegradable substrate (e.g.,silk)/silicone based polymer substrate with a high degree of stabilitycan be utilized for transdermal delivery (via a patch/passivemicropatch/active micropatch) of the topical composition (formulation)in Table-1C along with compositions described in previous paragraphs.

Furthermore, the topical composition (formulation) in Table-1C alongwith compositions described in previous paragraphs can be applied viasilk fibroin nanoparticles or a silk fibroin based patch or a pressuresensitive transdermal patch (e.g., a pressure sensitive single-layertransdermal/multi-layer/reservoir transdermal patch) or thepassive/active patch as described in later paragraphs

TABLE 1D Composition Of A Mixture Of Micronutrients - May Also IncludeSome Bioactive Compounds From Tables Before & After This Table Unit+/−50% WT % Botanicals Boswellia serrata Extract Mg 1000 12.62% CayennePepper Mg 200 2.52% Corydalis yanhusuo Root Concentrate Mg 200 2.52%Curcuma longa Root Extract Mg 200 2.52% Salix (White Willow) BarkExtract Mg 200 2.52% Zingiber officinale Root Concentrate Mg 200 2.52%Chemicals Chondroitin Sulfate Mg 1000 12.62% Curcumin(Nanoformulated)^(1,2) Mg 200 2.52% Dehydrocorybulbine (DHCB) Mg 1001.26% Geinstein Mg 100 1.26% Glucosamine Hydrochloride Mg 2000 25.25% OrGlucosamine Sulfate Hyaluronic Acid Mg 100 1.26% Methylsufonlymethane(MSM) Mg 1000 12.62% S-Adenosyl methionine (SAM) Mg 200 2.52%Sulforaphane Mg 400 5.05% Minerals Boron Mg 2 0.03% Calcium Mg 500 6.31%Copper Mg 1 0.01% Magnesium Mg 100 1.26% Manganese Mg 2 0.03% MolybdenumMg 0.1 0.00% Zinc (L-Opti) Mg 15 0.19% Vitamins Vitamin B₁₂(Methylcobalamin) Mg 1 0.01% Vitamin C Mg 200 2.52% Vitamin D IU 20000.00% Total Weight G 7.92 100.00%

TABLE 1E Composition Of A Mixture Of Micronutrients - May Also IncludeSome Bioactive Compounds From Tables Before & After This Table Unit+/−50% WT % Botanicals Boswellia serrata Extract Mg 1000 12.95%Corydalis yanhusuo Root Concentrate Mg 200 2.59% Curcuma longa RootExtract Mg 200 2.59% Salix (White Willow) Bark Extract Mg 200 2.59%Zingiber officinale Root Concentrate Mg 200 2.59% Chemicals ChondroitinSulfate Mg 1000 12.95% Curcumin (Nanoformulated)^(1,2) Mg 200 2.59%Dehydrocorybulbine Mg 100 1.30% Geinstein Mg 100 1.30% GlucosamineHydrochloride Mg 2000 25.90% Or Glucosamine Sulfate Hyaluronic Acid Mg100 1.30% Methylsufonlymethane Mg 1000 12.95% S-Adenosyl methionine Mg200 2.59% Sulforaphane Mg 400 5.18% Minerals Boron Mg 2 0.03% Calcium Mg500 6.48% Copper Mg 1 0.01% Magnesium Mg 100 1.30% Manganese Mg 2 0.03%Molybdenum Mg 0.1 0.00% Zinc (L-Opti) Mg 15 0.19% Vitamins Vitamin B₁₂(Methylcobalamin) Mg 1 0.01% Vitamin C Mg 200 2.59% Vitamin D IU 20000.00% Total Weight G 7.72 100.00%

TABLE 1F Composition Of A Mixture Of Micronutrients - May Also IncludeSome Bioactive Compounds From Tables Before & After This Table Unit+/−50% WT % Botanicals Boswellia serrata Extract Mg 1000 13.30% Curcumalonga Root Extract Mg 200 2.66% Salix (White Willow) Bark Extract Mg 2002.66% Zingiber officinale Root Concentrate Mg 200 2.66% ChemicalsChondroitin Sulfate Mg 1000 13.30% Curcumin (Nanoformulated)^(1,2) Mg200 2.66% Dehydrocorybulbine Mg 100 1.33% Geinstein Mg 100 1.33%Glucosamine Hydrochloride Mg 2000 26.59% Or Glucosamine SulfateHyaluronic Acid Mg 100 1.33% Methylsufonlymethane Mg 1000 13.30%S-Adenosyl methionine Mg 200 2.66% Sulforaphane Mg 400 5.32% MineralsBoron Mg 2 0.03% Calcium Mg 500 6.65% Copper Mg 1 0.01% Magnesium Mg 1001.33% Manganese Mg 2 0.03% Molybdenum Mg 0.1 0.00% Zinc (L-Opti) Mg 150.02% Vitamins Vitamin B₁₂ (Methylcobalamin) Mg 1 0.01% Vitamin C Mg 2002.66% Vitamin D IU 2000 0.05% Total Weight G 7.52 100.00%

TABLE 1G Composition Of A Mixture Of Micronutrients - May Also IncludeSome Bioactive Compounds From Tables Before & After This Table Unit+/−50% WT % Botanicals Boswellia serrata Extract Mg 1000 13.66% Salix(White Willow) Bark Extract Mg 200 2.73% Zingiber officinale RootConcentrate Mg 200 2.73% Chemicals Chondroitin Sulfate Mg 1000 13.66%Curcumin (Nanoformulated)^(1,2) Mg 200 2.73% Dehydrocorybulbine (DHCB)Mg 100 1.37% Geinstein Mg 100 1.37% Glucosamine Hydrochloride Mg 200027.32% Or Glucosamine Sulfate Hyaluronic Acid Mg 100 1.37%Methylsufonlymethane Mg 1000 13.66% S-Adenosyl methionine Mg 200 2.73%Sulforaphane Mg 400 5.46% Minerals Boron Mg 2 0.03% Calcium Mg 500 6.83%Copper Mg 1 0.01% Magnesium Mg 100 1.37% Manganese Mg 2 0.03% MolybdenumMg 0.1 0.00% Zinc (L-Opti) Mg 15 0.20% Vitamins Vitamin B₁₂(Methylcobalamin) Mg 1 0.01% Vitamin C Mg 200 2.73% Vitamin D IU 20000.00% Total Weight G 7.32 100.00%

TABLE 1H Composition Of A Mixture Of Micronutrients - May Also IncludeSome Bioactive Compounds From Tables Before & After This Table Unit+/−50% WT % Botanicals Boswellia serrata Extract Mg 1000 14.04% Zingiberofficinale Root Concentrate Mg 200 2.81% Chemicals Chondroitin SulfateMg 1000 14.04% Curcumin (Nanoformulated)^(1,2) Mg 200 2.81%Dehydrocorybulbine Mg 100 1.40% Geinstein Mg 100 1.40% GlucosamineHydrochloride Mg 2000 28.09% Or Glucosamine Sulfate Hyaluronic Acid Mg100 1.40% Methylsufonlymethane Mg 1000 14.04% S-Adenosyl methionine Mg200 2.81% Sulforaphane Mg 400 5.62% Minerals Boron Mg 2 0.03% Calcium Mg500 7.02% Copper Mg 1 0.01% Magnesium Mg 100 1.40% Manganese Mg 2 0.03%Molybdenum Mg 0.1 0.00% Zinc (L-Opti) Mg 15 0.21% Vitamins Vitamin B₁₂(Methylcobalamin) Mg 1 0.01% Vitamin C Mg 200 2.81% Vitamin D IU 20000.00% Total Weight G 7.12 100.00%

TABLE 1I Composition Of A Mixture Of Micronutrients - May Also IncludeSome Bioactive Compounds From Tables Before & After This Table Unit+/−50% WT % Botanicals Boswellia serrata Extract Mg 1000 14.45%Chemicals Chondroitin Sulfate Mg 1000 14.45% Curcumin(Nanoformulated)^(1,2) Mg 200 2.89% Dehydrocorybulbine Mg 100 1.44%Geinstein Mg 100 1.44% Glucosamine Hydrochloride Mg 2000 28.90% OrGlucosamine Sulfate Hyaluronic Acid M 100 1.44% Methylsufonlymethane Mg1000 14.45% S-Adenosyl methionine Mg 200 2.89% Sulforaphane Mg 400 5.78%Minerals Boron Mg 2 0.03% Calcium Mg 500 7.22% Copper Mg 1 0.01%Magnesium Mg 100 1.44% Manganese Mg 2 0.03% Molybdenum Mg 0.1 0.00% Zinc(L-Opti) Mg 15 0.22% Vitamins Vitamin B₁₂ (Methylcobalamin) Mg 1 0.01%Vitamin C Mg 200 2.89% Vitamin D IU 2000 0.00% Total Weight G 6.92100.00%

TABLE 1J Composition Of A Mixture Of Micronutrients - May Also IncludeSome Bioactive Compounds From Tables Before & After This Table Unit+/−50% WT % Botanical Boswellia serrata Extract Mg 1000 14.66% ChemicalsChondroitin Sulfate Mg 1000 14.66% Curcumin (Nanoformulated)^(1,2) Mg200 2.93% Geinstein Mg 100 1.47% Glucosamine Hydrochloride OrGlucosamine Mg 2000 29.32% Sulfate Hyaluronic Acid Mg 100 1.47%Methylsufonlymethane Mg 1000 14.66% S-Adenosyl methionine Mg 200 2.93%Sulforaphane Mg 400 5.86% Minerals Boron Mg 2 0.03% Calcium Mg 500 7.33%Copper Mg 1 0.01% Magnesium Mg 100 1.47% Manganese Mg 2 0.03% MolybdenumMg 0.1 0.00% Zinc (L-Opti) Mg 15 0.22% Vitamins Vitamin B₁₂(Methylcobalamin) Mg 1 0.01% Vitamin C Mg 200 2.93% Vitamin D IU 20000.00% Total Weight G 6.82 100.00%

TABLE 1K Composition Of A Mixture Of Micronutrients - May Also IncludeSome Bioactive Compounds From Tables Before & After This Table Unit+/−50% WT % Botanical Boswellia serrata Extract Mg 1000 15.10% ChemicalsChondroitin Sulfate Mg 1000 15.10% Curcumin (Nanoformulated)^(1,2) Mg200 3.02% Geinstein Mg 100 1.51% Glucosamine Hydrochloride OrGlucosamine Mg 2000 30.21% Sulfate Hyaluronic Acid Mg 100 1.51%Methylsufonlymethane Mg 1000 15.10% Sulforaphane Mg 400 6.04% MineralsBoron Mg 2 0.03% Calcium Mg 500 7.55% Copper Mg 1 0.02% Magnesium Mg 1001.51% Manganese Mg 2 0.03% Molybdenum Mg 0.1 0.00% Zinc (L-Opti) Mg 150.23% Vitamins Vitamin B₁₂ (Methylcobalamin) Mg 1 0.02% Vitamin C Mg 2003.02% Vitamin D IU 2000 0.00% Total Weight G 6.61 100.00%

500 mg of avocado soybean unsaponifiables (ASU) can be added tocompositions in Table-1D through Table-1K.

300 mg of black tart cherry extract can be added to compositions inTable-1D through Table-1K.

300 mg of pine bark extract can be added to compositions in Table-1Dthrough Table-1K.

TABLE 2A Composition Of A Mixture Of Antioxidants - May Also IncludeSome Bioactive Compounds From Tables Before & After This Table ChemicalsUnit +/−50% WT % Acetyl-L-Carnitine Mg 200 2.12% Alpha-R-Lipoic Acid Mg20 0.21% Coenzyme Q₁₀ (Nanoformulated)^(1,2) Mg 200 2.12% D-Ribose Mg400 4.25% Epigallocatechin Gallate Mg 200 2.12% Ferulic Acid Mg 2002.12% Hyaluronic Acid Mg 200 2.12% Inositol Hexanicotinate Mg 200021.23% Isothiocyanate Sulforaphane Mg 200 2.12% L-Arginine Mg 400042.46% L-Analyl-L-Glutamine Mg 200 2.12% L-Glutamine Mg 200 2.12%L-Glutathione Mg 200 2.12% (Or Ebselen Or N-Acetyl-L-Cysteine)Pterostilbene (Nanoformulated)^(1,2) Mg 200 2.12% Quercetin(Nanoformulated)^(1,2) Mg 200 2.12% Resveratrol (Nanoformulated)^(1,2)Mg 200 2.12% Superoxide Dismutase* (Nanoformulated)^(1,2) Mg 200 2.12%Ubiquinol (Nanoformulated)^(1,2) Mg 400 4.25% Total Weight G 9.42100.00%

TABLE 2B Additional Composition Of A Mixture Of Antioxidants - May AlsoInclude Some Bioactive Compounds From Tables Before & After This TableBotanicals Unit +/−50% WT % Aronia melanocarpa ⁺ Mg 200 12.50% Citruslimonum ⁺ Mg 200 12.50% Daucus carota ⁺ Mg 200 12.50% Hibiscus spp.⁺ Mg200 12.50% Malus domestica ⁺ Mg 200 12.50% Ribes nigrum ⁺ Mg 200 12.50%Sambucus nigra ⁺ Mg 200 12.50% Vaccinium spp.⁺ Mg 200 12.50% TotalWeight G 1.60 100.00%

TABLE 3A Composition Of A Multi-Serve Antioxidant Liquid - May AlsoInclude Some Bioactive Compounds From Tables Before & After This TableUnit +/−50% WT % Botanicals Actinidia chinenesis ⁺ G 25 5.49% Ananascomosus ⁺ G 25 5.49% Cocos nucifera ⁺ G 350 76.88% Garcinia mangostana ⁺G 25 5.49% Litchi chinensis ⁺ G 25 5.49% Vitis spp.⁺ G 0.75 0.16%Chemicals Citicoline G 0.75 0.16% (Or L-Alpha Glycerylphosphorylcholine)Coenzyme Q₁₀ (Nanoformulated)^(1,2) G 0.75 0.16% D-Ribose G 0.75 0.16%L-Analyl-L-Glutamine G 0.75 0.16% L-Theanine G 0.75 0.16% Ubiquinol(Nanoformulated)^(1,2) G 0.75 0.16% Total Weight G 455.25 100.00%

TABLE 3B Composition Of A Single-Serve Antioxidant Liquid - May AlsoInclude Some Bioactive Compounds From Tables Before & After This TableUnit +/−50% WT % Chemicals Citicoline (Or L-Alpha G 0.25 0.05%Glycerylphosphorylcholine) Coenzyme Q₁₀ (Nanoformulated)^(1,2) G 0.250.05% Creatine G 2.0 0.44% D-Ribose G 0.25 0.05% Gamma-Aminobutyric AcidG 0.25 0.05% Inulin G 5 1.09% L-Analyl-L-Glutamine G 0.25 0.05%L-Theanine G 0.25 0.05% Melatonin (Extended Release) G 0.002 0.00% Omega3-6-9 Acid (Including G 0.25 0.05% Decosahexanoic Acid)(Nanoformulated)¹ Plant Sterol (Nanoformulated)¹ G 5 1.09% Ubiquinol(Nanoformulated)^(1,2) G 0.25 0.05% Uridine G 0.25 0.05% SweetenersErythritol G 10 2.18% Stevia rebaudiana ⁺ G 0.025 0.01% Trehalose G 0.250.05% Others Acidified Coconut Water (&/Or Aloe Vera G 435 94.66% Juice&/Or Filter Water) Live Lactobacillus plantarum 299v Billion 10 0.00%Total Weight G 459.52 100.00%

TABLE 3C Composition Of A Single-Serve Antioxidant Liquid - May AlsoInclude Some Bioactive Compounds From Tables Before & After This TableUnit +/−50% WT % Botanicals Aronia melanocarpa ⁺ G 0.25 0.05% Citruslimonum ⁺ G 0.25 0.05% Daucus carota ⁺ G 0.25 0.05% Hibiscus spp.⁺ G0.25 0.05% Malus domestica ⁺ G 0.25 0.05% Ribes nigrum ⁺ G 0.25 0.05%Sambucus nigra ⁺ G 0.25 0.05% Vaccinium spp.⁺ G 0.25 0.05% ChemicalsCiticoline (Or L-Alpha G 0.25 0.05% Glycerylphosphorylcholine) CoenzymeQ₁₀ (Nanoformulated)^(1,2) G 0.25 0.05% Creatine G 2.0 0.43% D-Ribose G0.25 0.05% Gamma-Aminobutyric Acid G 0.25 0.05% Inulin G 5 1.08%L-Analyl-L-Glutamine G 0.25 0.05% L-Theanine G 0.25 0.05% Melatonin(Extended Release) G 0.002 0.00% Omega 3-6-9 Acid (Including G 0.250.05% Decosahexanoic Acid) (Nanoformulated)¹ Plant Sterol(Nanoformulated)¹ G 5 1.08% Ubiquinol (Nanoformulated)^(1,2) G 0.250.05% Uridine G 0.25 0.05% Sweeteners Erythritol G 10 2.17% Steviarebaudiana ⁺ G 0.025 0.01% Trehalose G 0.25 0.05% Others AcidifiedCoconut Water (&/Or Aloe Vera G 435 94.25% Juice &/Or Filter Water) LiveLactobacillus plantarum 299v Billion 10 0.00% Total Weight G 461.52100.00%

TABLE 3D Composition Of Botanicals - May Also Include Some BioactiveCompounds From Tables Before & After This Table Unit +/−50% WT %Botanicals Chamomilla recutita Mg 200 6.66% Humulus lupulus Mg 200 6.66%Lavandula angustifolia Mg 200 6.66% Melissa officinalis Mg 200 6.66%Passiflora incarnate Mg 200 6.66% Valeriana officinalis Mg 200 6.66%Chemicals Bromelain Mg 400 13.32% Citicoline (Or L-Alpha Mg 200 6.66%Glycerylphosphorylcholine) Gamma-Aminobutyric Acid Mg 200 6.66%L-Theanine Mg 200 6.66% L-Tryptophan Mg 800 26.64% Melatonin (ExtendedRelease) Mg 3 0.10% Others Unit Live Bifidobacterium longum Billion 100.00% Live Lactobacillus helveticus Billion 10 0.00% Total Weight G 3.00100.00%

TABLE 3E Composition Of A Mixture Of Electrolytes & Dextrose - May AlsoInclude Some Bioactive Compounds From Tables Before & After This TableNutrients Unit Per 8 Fluid Oz Sodium 10.6 mEq Potassium  4.7 mEqChloride  8.3 mEq Zinc  1.9 Mg Dextrose  5.9 GSmart Container

Suitable biodegradable material (e.g., silk/plant derived plasticmaterial) can be used as a container.

Lignin (or lignen) is an integral complex chemical compound of thesecondary cell walls of plants. A plant derived plastic can be based onlignin (or lignen) as a base material.

Furthermore, lignin (or lignen) can be integrated (multi-layered) withchitin (a biopolymer based on the N-acetyl-glucosamine monomer) and/orchitin's variant deacetylated counterpart chitosan and/or fibroin (aprotein derived from silk) as a base material.

TABLE 4 Compositions Of A Biodegradable Plastic Material Wt % Wt % Wt %Wt % Compositions Material A Material B Material C Material D 1 80%Lignin 20% Chitin 2 80% Lignin 20% Chitosan 3 80% Lignin 10% Chitin 10%Chitosan 4 80% Lignin 20% Fibroin 5 80% Lignin 10% Chitin 10% Fibroin 680% Lignin 10% Chitosan 10% Fibroin 7 80% Lignin 10% Chitosan 10%Fibroin 8 80% Lignin 5% Chitosan 5% Chitosan 10% Fibroin

A lens/an array of lenses (e.g., utilizing silk material) can beintegrated on the interior wall of the container to detect thepresence/growth of bacteria/microbes (e.g., bacteria/microbes in aliquid mixture).

Furthermore, the lens/array of lenses (e.g., utilizing silk material)can be integrated with a biological colony counter to estimate/countgood/bad bacteria.

One-Dimensional/two-dimensional barcode/quick response (QR) codes and/ora radio frequency identification device (RFID) active/passive tag and/ora near-field communication (NFC) tag and/or an ultra-lower powerconsumption microprocessor (e.g., an Ambiqmicro ARM Cortex™-M3microcontroller or an organic transistor based microprocessor ornano-scaled InAs XOI based microprocessor or Freescale 2 millimeters×2millimeters KL02 chip-scale package (CSP) (chip-scale package with thecomponents of a micro-scaled computer can be configured with a microIP/light weight IP address) and/or a memory/storage component (e.g., aprinted memristor on a flexible substrate) and a thin-film printedbattery/miniature solar cell component can be integrated on an exteriorlabel (covers only a segment of the container's exterior) to (a) deliverinformation about the product, (b) advertise (e.g., click to view moreproduct (e.g., a drug) information linked with a website and/or click toreceive a product coupon in near real-time/real-time), (c) interact(e.g., collective quorum vote on user liking/disliking of the product innear real-time/real-time) with a user's portable internet appliance(e.g., a smart phone/tablet personal computer) and (d) communicate withan inventory management system and/or smart shopping cart, wherein thesmart shopping cart is configured (with a removable (about seven (7)inch) display device integrated with a near-field communication tag anda near-field communication reader) to determine the user's commercialidentity/personality on the doorway entrance of the retailer.

Furthermore, the retail location can be enabled with sensors, augmentedreality and computer vision (including self-learning computer vision)for enhanced experience of the user.

In another embodiment, a smart refrigerator containing (food) packages(wherein each package is integrated with a usage indicator microchip)can communicate (wirelessly) with an internet connected homegateway/storage subsystem. Thus, the home gateway/storage subsystem cancommunicate (wirelessly) with the user's portable internet applianceprior to any shopping.

The user's commercial identity/personality can be enhanced by acollection of inputs from statistically similar users in nearreal-time/real-time and these inputs can be analyzed by data mining, ANN(artificial neural networks), hierarchical cluster analysis and KNN(K-nearest neighbor analysis) and intelligent learning algorithm. Theseinputs can complement/enhance the user's commercialidentity/personality.

Furthermore, these inputs can include the user's facial recognitionprofile (wherein a facial data is converted into a mathematical code ora pattern) to complement/enhance the user's commercialidentity/personality.

The user experience can be further enhanced by artificial intelligence(including self-learning artificial intelligence), computer vision(including self-learning computer vision), data mining,fuzzy/neuro-fuzzy logic, machine vision (including self-learning machinevision), natural language processing, neural networks (includingself-learning neural networks), pattern recognition, reasoning modelingand self-learning (including evidence based self-learning).

It should be noted that artificial intelligence (including self-learningartificial intelligence), computer vision (including self-learningcomputer vision), data mining, fuzzy/neuro-fuzzy logic, machine vision(including self-learning machine vision), natural language processing,neural networks (including self-learning neural networks), patternrecognition, reasoning modeling and self-learning (including evidencebased self-learning) can be enhanced by quantum computing or quantumcomputing based machine learning.

The exterior label can be integrated with thermochromic ink dot toindicate the temperature of the container.

The exterior label can be placed on a heat-dissipating thermallyconducting flexible polymer film. Furthermore, the thermally conductingflexible polymer film can be integrated with a barrier thin-film (e.g.,100 nanometers thick alumina (Al₂O₃) fabricated/constructed, utilizing alow-temperature atomic layer deposition (ALD) process).

Humidity, oxygen and water can slowly diffuse into the container todegrade the liquid mixture over time. The barrier thin-film can preventagainst humidity, oxygen and water.

The container can be suitably (about 15 degrees' centigrade hot-coldside temperature difference) heated or cooled by an array of (embeddedsuperlattice based thin-film Pettier) thermoelectrics, herein thethermoelectrics can be integrated (by utilizingLithographie-Galvanoformung-Abformung (LIGA), electroforming andmicroelectro-mechanical-system process) on the heat-dissipatingthermally conducting flexible polymer film. The thermoelectrics coversonly a section of the container's exterior.

Thermal resistance between the thermoelectrics and thermally conductingflexible polymer film is a critical parameter for an efficient heatingand/or cooling.

The array of thermoelectrics can be electrically powered by an array ofprinted thin-film batteries/titanium dioxide solar cells (with porphyrindyes).

TABLE 5 Composition Of A Mixture For Expression Of Beneficial NrF2Protein - May Also Include Some Bioactive Compounds From Tables Before &After This Table (Except Table-4 and Table-6) Botanicals Unit +/−50% WT% Astragalus membranaceus ⁺ Mg 200 6.25% Bacopa monnieri ⁺ Mg 200 6.25%Camellia sinensis ⁺ (Black) Mg 200 6.25% Camellia sinensis ⁺ (Green) Mg200 6.25% Curcuma longa ⁺ (Or A Curcuminoids Mg 400 12.50%Compound)^(1,2,3,4) Euterpe oleracea ⁺ Mg 200 6.25% Hippophae rhamnoides⁺ Mg 200 6.25% Lycium barbarum ⁺ Mg 200 6.25% Phyllanthus emblica ⁺ Mg200 6.25% Punica granatum ⁺ Mg 200 6.25% Silybum marianum ⁺ Mg 200 6.25%Tinospora cordifolia ⁺ Mg 200 6.25% Vitis spp.⁺ Mg 200 6.25% Wasabiajaponica ⁺ Mg 200 6.25% Withania somnifera ⁺ Mg 200 6.25% Total Weight G3.20 100.00%

Mitochondria are both generators of and targets for reactive molecularspecies. Therefore, oxidative stress is intimately linked withmitochondrial dysfunction. The abundant mitochondria in a human brainare major sites of generation and action of reactive oxygenspecies/reactive nitrogen species (RNS), since a human brain utilizesabout 20% of the inspired oxygen and 90% of the consumed oxygen toproduce energy during oxidative phosphorylation. Thus, a human brain isparticularly sensitive to free radical damage/oxidative stress.Mitochondrial turnover is dependent on autophagy (meaning self-eating),which declines with age and is frequently dysfunctional in manyneurodegenerative diseases (including Alzheimer's). Autophagy can engagein cross-talk with reactive oxygen species/reactive nitrogen species inboth cell signaling and protein damage. The mammalian Target ofRapamycin is an autophagy pathway. The mammalian Target of Rapamycinpathway can function as an inhibitor of the initiation process ofautophagy.

Alzheimer's, Cardiovascular and Type-2 Diabetes diseases have misfoldedand they all have damaged proteins triggered by pathology at themolecular level. There are about 100,000 different proteins in a humanbody. After each protein is synthesized, it must be folded into theright shape to be functional. Mistakes can happen, that is why cellshave sophisticated housekeeping mechanisms to repair or destroy poorlyformed proteins before they can do any harm. Occasionally, a misfoldedprotein can evade these sophisticated housekeeping mechanisms andaccumulates in sufficient quantities to clump together to damage/killthe cell.

One way to treat Alzheimer's, Cardiovascular and Type-2 Diabetesdiseases, caused by misfolded proteins is to stimulate the housekeepingmechanisms by activating autophagy (or alternatively,suppressing/inhibiting the mammalian Target of Rapamycin).

As a central controller of cell growth and nutrient sensor, themammalian Target of Rapamycin plays a key role in aging, Alzheimer's,Cardiovascular and Diabetes diseases.

Furthermore, AMPK up regulation (via bioactive compounds and/orbioactive molecules in Momordica charantia) activates autophagy via dualmechanisms involving not only by suppressing/inhibiting the mammalianTarget of Rapamycin (in particular the mammalian Target of RapamycinC1), but also by direct phosphorylation of ULK1 protein.

The bioactive compounds 100 and/or bioactive molecules 100A tosuppress/inhibit the mammalian Target of Rapamycin can beencapsulated/caged in the nanoshell 120.

The nanoshell 120 decorated with a targeting ligand, wherein thetargeting ligand can recognize/match/bind with adenosine receptors—thusallowing a human body's blood-brain barrier (BBB) to be opened for thepassage of the nanoshell 120 to deliver the bioactive compounds 100and/or bioactive molecules 100A to suppress/inhibit the mammalian Targetof Rapamycin in a human brain.

TABLE 6 Molecular Docking Score With The Mammalian Target Of RapamycinUtilizing Computational Chemistry Software (Also Illustrated In FIG. 5Aand 5B) Chemicals Molecular Score Rapamycin/Sirolimus (Known ToSuppress/Inhibit The −8.64 Mammalian Target Of Rapamycin) Withaferin A−7.04 Cycloastragenol −2.27 Bisdemethoxycurcumin −1.86 Curcumin −1.82Vitamin D₃ −1.72 Verbascoside −1.13 Momordin −0.86 SMER-28 −0.71Resveratrol −0.31 Epigallocatechin gallate −0.28 Trehalose (Can InduceAutophagy Independent Of −0.25 The Mammalian Target Of Rapamycin)N,N-dimethylimidodicarbonimidic diamide −0.11 (Metformin)

Rapamycin can generate buildup of fatty acids and eventually an increasein insulin resistance leading to Type-2 Diabetes disease. But acombination of rapamycin and metformin can reduce insulin resistance andtreat aging related diseases.

Furthermore, the combination of rapamycin and metformin can be enhancedin its efficacy and synergy by adding one or more chemicals (of suitableamount(s)): withaferin A, cycloastragenol, bisdemethoxycurcumin,curcumin, vitamin D3, verbascoside, momordin, SMER-28, resveratrol,epigallocatechin gallate and trehalose.

Alternatively, the above combination of rapamycin and metformin can besuitably replaced in its efficacy and synergy by one or more (ofsuitable amount(s)): withaferin A, cycloastragenol,bisdemethoxycurcumin, curcumin, vitamin D₃, verbascoside, momordin,SMER-28, resveratrol, epigallocatechin gallate and trehalose withmetformin.

TABLE 7A Composition Of A Mixture For Suppressing/Inhibiting TheMammalian Target Of Rapamycin - May Also Include Some BioactiveCompounds From Tables Before & After This Table Unit +/−50% WT %Botanical Momordica charantia+ Mg 200 20.00% Chemicals Withaferin A (OrA Chemical Derivative Or Mg 400 40.00% A Structural Analog Of WithaferinA) (Nanoformulated)^(1,2) Withanolides (Or A Chemical Derivative Or Mg200 20.00% A Structural Analog Of Withanolides) (Nanoformulated)^(1,2)Withanosides (Or A Chemical Derivative Or Mg 200 20.00% A StructuralAnalog Of Withanosides) (Nanoformulated)^(1,2) Total Weight G 1.00100.00%

TABLE 7B Composition Of A Mixture For Suppressing/Inhibiting TheMammalian Target Of Rapamycin - May Also Include Some BioactiveCompounds From Tables Before & After This Table Unit +/−50% WT %Botanical Momordica charantia+ Mg 200 12.50% ChemicalsBisdemethoxycurcumin (Nanoformulated)^(1,2) Mg 200 12.50% Curcumin(Nanoformulated)^(1,2,3,4) Mg 200 12.50% Cycloastragenol(Nanoformulated)^(1,2) Mg 200 12.50% Withaferin A (Or A ChemicalDerivative Or Mg 400 25.00% A Structural Analog Of Withaferin A)^(1,2)Withanolides (Or A Chemical Derivative Or Mg 200 12.50% A StructuralAnalog Of Withanolides) (Nanoformulated)^(1,2) Withanosides (Or AChemical Derivative Or Mg 200 12.50% A Structural Analog OfWithanosides) (Nanoformulated)^(1,2) Vitamin Vitamin D₃(Cholecalciferol) Mg 0.06 0.00% Total Weight G 1.60 100.00%

TABLE 7C Composition Of A Mixture For Suppressing/Inhibiting TheMammalian Target Of Rapamycin - May Also Include Some BioactiveCompounds From Tables Before & After This Table Unit +/−50% WT %Botanical Momordica charantia ⁺ Mg 200 7.66% Chemicals6-Bromo-N-2-propenyl-4-quinazolinamine Mg 10 0.38% (SMER-28)Bisdemethoxycurcumin (Nanoformulated)^(1,2) Mg 200 7.66% Curcumin(Nanoformulated)^(1,2,3,4) Mg 200 7.66% Cycloastragenol(Nanoformulated)^(1,2) Mg 200 7.66% Epigallocatechin gallate Mg 2007.66% Momordin Mg 200 7.66% Resveratrol (Nanoformulated)^(1,2) Mg 2007.66% Trehalose Mg 200 7.66% Verbascoside Mg 200 7.66% Withaferin A (OrA Chemical Derivative Or Mg 400 15.33% A Structural Analog Of WithaferinA) (Nanoformulated)^(1,2) Withanolides (Or A Chemical Derivative Or Mg200 7.66% A Structural Analog Of Withanolides) (Nanoformulated)^(1,2)Withanosides (Or A Chemical Derivative Or Mg 200 7.66% A StructuralAnalog Of Withanosides) (Nanoformulated)^(1,2) Vitamin Vitamin D₃(Cholecalciferol) Mg 0.06 0.00% Total Weight G 2.61 100.00%

TABLE 7D Composition Of A Mixture For Suppressing/Inhibiting TheMammalian Target Of Rapamycin - May Also Include Some BioactiveCompounds From Tables Before & After This Table Unit +/−50% WT %Botanicals Cinnamomum zeylanicum ⁺ Mg 200 6.67% Momordica charantia ⁺ Mg200 6.67% Vitis vinifera ⁺ (e.g., Seed Extract) Mg 200 6.67% ChemicalsBisdemethoxycurcumin (Nanoformulated)^(1,2) Mg 200 6.67% Curcumin(Nanoformulated)^(1,2,3,4) Mg 200 6.67% Cycloastragenol(Nanoformulated)^(1,2) Mg 200 6.67% Epigallocatechin gallate Mg 2006.67% Momordin Mg 200 6.67% N,N-dimethylimidodicarbonimidic diamide Mg200 6.67% (Or Chemical Derivative Or Structural Analog Of N,N-dimethylimidodicarbonimidic diamide) Proanthocyanidins Mg 200 6.67%Resveratrol (Nanoformulated)^(1,2) Mg 200 6.67% Withaferin A (Or AChemical Derivative Or Mg 400 13.33% A Structural Analog Of WithaferinA) (Nanoformulated)^(1,2) Withanolides (Or A Chemical Derivative Or Mg200 6.67% A Structural Analog Of Withanolides) (Nanoformulated)^(1,2)Withanosides (Or A Chemical Derivative Or Mg 200 6.67% A StructuralAnalog Of Withanosides) (Nanoformulated)^(1,2) Vitamin Vitamin D₃(Cholecalciferol) Mg 0.06 0.00% Total Weight G 3.00 100.00%

TABLE 8A Composition Of A Mixture For Lowering The Risks Of Alzheimer'sDisease - May Also Include Some Bioactive Compounds From Tables Before &After This Table Unit +/−50% WT % Botanicals Bacopa monnieri ⁺ Mg 2002.01% Boswellia serrata ⁺¹ Mg 200 2.01% Camellia sinensis ⁺ (Black) Mg200 2.01% Camellia sinensis ⁺ (Green) Mg 200 2.01% Cinnamomum zeylanicum⁺ Mg 200 2.01% Curcuma longa ⁺ (Or A Curcuminoids Mg 400 4.01%Compound)^(1,2,3,4) Emblica officinalis ⁺ Mg 200 2.01% Mucuna pruriens ⁺Mg 200 2.01% Paeoniae alba ⁺ Mg 200 2.05% Panax quinquefolius ⁺ Mg 2002.01% Polygala tenuifolia ⁺ Mg 200 2.01% Rosmarinus officinalis ⁺ Mg 2002.01% Silybum marianum ⁺ Mg 200 2.01% Vitis vinifera ⁺ Mg 200 2.01%Withania somnifera ⁺ Mg 200 2.01% Chemicals Acetylcholine (Or Choline OrPhosphatidyl Mg 200 2.01% Choline) Alpha-R-Lipoic Acid Mg 20 0.20%Aniracetam (Or Piracetam) Mg 200 2.01% Caffeine Mg 20 0.20% Citicoline(Or L-Alpha Mg 200 2.01% Glycerylphosphorylcholine) Coenzyme Q₁₀(Nanoformulated)^(1,2) Mg 200 2.01% DMAE (Dimethyl Amino Ethanol) Mg 2002.01% Epigallocatechin gallate Mg 200 2.01% Fisetin Mg 200 2.01%Huperzine A Mg 200 2.01% L-Arginine Mg 200 2.01% L-Carnosine Mg 2002.01% L-Dopa Mg 100 1.00% L-Glutathione (Or Ebselen Or N-Acetyl-L- Mg200 2.01% Cysteine) L-Theanine Mg 200 2.01% L-Tyrosine (Or M-Tyrosine OrN-Acetyl Mg 200 2.01% Tyrosine) Melatonin (Extended Release) Mg 3 0.03%N-Acetyl-L-Carnitine Mg 400 4.01% Omega 3-6-9 Acid (Including Mg 2002.01% Decosahexanoic Acid) (Nanoformulated)^(1,2) Picamilon Mg 200 2.01%Phosphatidylserine Mg 200 2.01% Pyrroloquinoline Quinone Mg 20 0.20%(Nanoformulated)^(1,2) Quercetin^(1,2) Mg 200 2.01% Resveratrol^(1,2) Mg200 2.01% Tetramethylpyrazine (TMP) Mg 200 2.01% Trehalose Mg 200 2.01%Ubiquinol (Nanoformulated)^(1,2) Mg 1000 10.03% Uridine Mg 200 2.01%Vinpocetine Mg 200 2.01% Withaferin A (Or Chemical Derivative Or Mg 4004.01% Structural Analog Of Withaferin A) (Nanoformulated)^(1,2) MineralMagnesium L-Threonate Mg 400 4.01% Vitamins Vitamin B₁₂(Methylcobalamin) Mg 1 0.01% Vitamin D₃ Mg 0.25 0.00% Vitamin K₂ Mg 2.00.02% Total Weight G 9.97 100.00%

TABLE 8B Additional Composition Of A Mixture For Lowering The Risks OfAlzheimer's Disease - May Also Include Some Bioactive Compounds FromTables Before & After This Table Unit +/−50% WT % Botanicals Bacopamonnieri ⁺ Mg 200 2.16% Boswellia serrata ⁺¹ Mg 200 2.16% Chamomillarecutita Mg 200 2.16% Cinnamomum zeylanicum ⁺ Mg 200 2.16% Curcuma longa⁺ (Or A Curcuminoids Mg 400 4.33% Compound)^(1,2,3,4) Humulus lupulus Mg200 2.16% Melissa officinalis Mg 200 2.16% Passiflora incarnate Mg 2002.16% Silybum marianum ⁺ Mg 200 2.16% Valeriana officinalis Mg 200 2.16%Withania somnifera ⁺ Mg 200 2.16% Chemicals Acetylcholine (Or Choline OrPhosphatidyl Mg 200 2.16% Choline) Caffeine Mg 20 0.22% Citicoline (OrL-Alpha Mg 200 2.16% Glycerylphosphorylcholine) Coenzyme Q₁₀(Nanoformulated)^(1,2) Mg 200 2.16% L-Glutathione (Or Ebselen OrN-Acetyl-L- Mg 200 2.16% Cysteine) L-Theanine Mg 200 2.16% L-Tyrosine(Or M-Tyrosine Or N-Acetyl Mg 200 2.16% Tyrosine) Melatonin (ExtendedRelease) Mg 3 0.03% N-Acetyl-L-Carnitine Mg 400 4.33% Omega 3-6-9 Acid(Including Mg 200 2.16% Decosahexanoic Acid) (Nanoformulated)^(1,2)Phosphatidylserine Mg 200 2.16% Pyrroloquinoline Quinone Mg 20 0.22%(Nanoformulated)^(1,2) Quercetin (Nanoformulated)^(1,2) Mg 200 2.16%Resveratrol (Nanoformulated)^(1,2) Mg 200 2.16% Tetramethylpyrazine(TMP) Mg 200 2.16% Trehalose Mg 200 2.16% Ubiquinol(Nanoformulated)^(1,2) Mg 1000 10.82% Uridine Mg 200 2.16% Withaferin A(Or Chemical Derivative Mg 400 4.33% Or Structural Analog Of WithaferinA) (Nanoformulated)^(1,2) Mineral Magnesium L-Threonate Mg 400 4.33%Vitamins Vitamin B₁₂ (Methylcobalamin) Mg 1 0.01% Vitamin D₃ Mg 0.250.00% Vitamin K₂ Mg 2.0 0.02% Other Lactoferrin Mg 2000 21.63% TotalWeight G 9.25 100.00%

⁺¹ Boswellia serrata can suppress/inhibit 5-lipoxygenase. A bioactivecompound (e.g., 3-O-acetyl-11-keto-β-boswellic acid) of Boswelliaserrata's can be nanoformulated to improve its bioavailability.

TABLE 8C Additional Composition Of A Mixture For Lowering The Risks OfAlzheimer's Disease - May Also Include Some Bioactive Compounds FromTables Before & After This Table Unit +/−50% WT % Botanicals Tinosporacordifolia ⁺ Mg 200 5.20% Withania somnifera ⁺ Mg 200 5.20% ChemicalsCaffeine Mg 20 0.52% Citicoline (Or L-Alpha Mg 400 10.40%Glycerylphosphorylcholine) Curcumin (Nanoformulated)^(1,2,3,4) Mg 2005.20% Decosahexanoic Acid Mg 400 10.40% L-Glutathione (Or Ebselen OrN-Acetyl-L- Mg 200 5.20% Cysteine) L-Theanine Mg 200 5.20% Melatonin(Extended Release) Mg 3 0.03% Pyrroloquinoline Quinone Mg 20 0.52%(Nanoformulated)^(1,2) Quercetin^(1,2) Mg 200 5.20% Ubiquinol Mg 100026.01% Withaferin A (Or Chemical Derivative Or Mg 400 10.40% StructuralAnalog Of Withaferin A) (Nanoformulated)^(1,2) Mineral MagnesiumL-Threonate Mg 400 10.40% Vitamins Vitamin D₃ Mg 0.25 0.01% Vitamin K₂Mg 2.0 0.05% Total Weight G 3.85 100.00%

L-Theanine & melatonin combination for the night time dose, whileL-Theanine and caffeine (or only caffeine) for the day time dose.

TABLE 8D Additional Composition Of A Mixture For Lowering The Risks OfAlzheimer's Disease - May Also Include Some Bioactive Compounds FromTables Before & After This Table Unit +/−50% WT % Botanicals Bacopamonnieri ⁺ Mg 200 5.46% Sceletium tortuosum ⁺ Mg 20 0.55% Withaniasomnifera ⁺ Mg 200 5.46% Chemicals Caffeine Mg 20 0.55% Citicoline (OrL-Alpha Mg 400 10.91% Glycerylphosphorylcholine) Curcumin(Nanoformulated)^(1,2,3,4) Mg 200 5.46% Decosahexanoic Acid Mg 40010.91% L-Glutathione (Or Ebselen Or N-Acetyl-L- Mg 200 5.46% Cysteine)Melatonin (Extended Release) Mg 3 0.08% Oleocanthal (Or A ChemicalDerivative Or Mg 200 5.46% A Structural Analog Of Oleocanthal)(Nanoformulated)^(1,2) Pyrroloquinoline Quinone Mg 20 0.55%(Nanoformulated)^(1,2) Ubiquinol Mg 1000 27.28% Withaferin A (OrChemical Derivative Or Mg 400 10.91% Structural Analog Of Withaferin A)(Nanoformulated)^(1,2) Mineral Magnesium L-Threonate Mg 400 10.91%Vitamins Vitamin D₃ Mg 0.25 0.01% Vitamin K₂ Mg 2.0 0.05% Total Weight G3.67 100.00%

TABLE 8E Additional Composition Of A Mixture For Lowering The Risks OfAlzheimer's Disease - May Also Include Some Bioactive Compounds FromTables Before & After This Table Chemicals Unit +/−50% WT %4,5-Bis-(4-methoxyanilino)phthalimide Mg 20 6.78%6-Bromoindirubin-3′-oxime² Mg 10 3.39%6-Bromo-N-2-propenyl-4-quinazolinamine Mg 10 3.39% (SMER-28)3,6-Dibromo-α-[(phenylamino)methyl]-9H- Mg 20 6.78% carbazole-9-ethanolLithium (Lithium Orotate Or Lithium Mg 5 1.69% Chloride) SodiumPhenylbutyrate² Mg 10 3.39% Uric Acid (From Inosine: Hypoxanthine Mg 206.78% Ribose) (+/−)-1-(1-Benzo[b]thien-2-ylethyl)-1- Mg 200 67.80%hydroxyurea Total Weight G 0.29 100.00%

TABLE 9 Composition Of A Mixture For Lowering The Risks OfCardiovascular Disease - May Also Include Some Bioactive Compounds FromTables Before & After This Table Unit +/−50% WT % Botanicals Alliumsativum ⁺ Mg 200 1.44% Crataegus oxyacantha ⁺ Mg 200 1.44% Inularacemosa ⁺ Mg 200 1.44% Olea europaea ⁺ Mg 200 1.44% Rauwolfiaserpentina ⁺ Mg 200 1.44% Terminalia arjuna ⁺ Mg 200 1.44% ChemicalsCapsaicin (Or Capsinoid) Mg 200 1.44% Chromium Polynicotinate Mg 0.20.00% Cocoa Flavanols Mg 400 2.88% Coenzyme Q₁₀ (Nanoformulated)^(1,2)Mg 1000 7.19% L-Arginine (Nanoformulated)^(1,2) Mg 1000 7.19%L-Glutathione (Or Ebselen Or N-Acetyl-L- Mg 200 1.44% Cysteine) PlantSterols (Nanoformulated)¹ Mg 5000 35.97% Red Yeast Rice Extract Mg 250017.99% Ubiquinol (Nanoformulated)^(1,2) Mg 1000 7.19% Mineral MagnesiumMg 400 2.88% Others Coconut Oil Mg 1000 7.19% Lactobacillus reuteriBillion 10 0.00% Total Weight G 13.90 100.00%

Table-9 can include 200 mg of Commiphora mukul extract.

TABLE 10A Composition Of A Mixture For Lowering The Risks Of Type-2Diabetes Disease - May Also Include Some Bioactive Compounds From TablesBefore & After This Table Unit +/−50% WT % Botanicals Andrographispaniculata ⁺ Mg 200 4.00% Artemisia princeps ⁺ Mg 200 4.00% Camelliasinensis ⁺ (Black) Mg 200 4.00% Camellia sinensis ⁺ (Green) Mg 200 4.00%Curulluma fimbrtara ⁺ Mg 200 4.00% Cinnamomum zeylanicum ⁺ Mg 200 4.00%Coccinia indica ⁺ Mg 800 16.00% Irvingia gabonensis ⁺ Mg 200 4.00%Lagerstroemia speciosa ⁺ (Leaf Extract) Mg 50 1.00% Litchi chinensis ⁺Mg 200 4.00% Momordica charantia ⁺ Mg 200 4.00% Salacia oblonga ⁺ Mg 80016.00% Chemicals Beta Glucan Mg 200 4.00% Chromium Polynicotinate Mg 0.20.0% Chlorogenic Acid Mg 200 4.00% Nobiletin (Or 2000 Mg Naringenin) Mg200 4.00% Touchi Mg 1000 20.00% Total Weight G 5.00 100.00%

Chlorogenic acid (CHA) is an activator of calcineurin.

TABLE 10B Composition Of A Mixture For Lowering The Risks Of Type-2Diabetes Disease - May Also Include Some Bioactive Compounds From TablesBefore & After This Table Unit +/−50% WT % Botanicals Andrographispaniculata ⁺ Mg 200 2.63% Artemisia princeps ⁺ Mg 200 2.63% Cocciniacordifolia ⁺ Mg 200 2.63% Cordyceps sinensis ⁺ Mg 200 2.63% Green CoffeeBean Extract Mg 1200 15.79% Lamon Variety Borlotto Bean Extract Mg 2002.63% Paecilomyces hepiali (Providing 70 mg Of Mg 1000 13.16% CordycepicAcid) Momordica charantia ⁺ Mg 200 2.63% Salacia oblonga ⁺ Mg 800 10.53%Sorghum bicolor ⁺ Mg 1000 13.16% White Mulberry (Providing 1- Mg 4005.26% deoxynojirinmycin 15 (DNJ) mg) Extract Chemicals Beta Glucan Mg200 2.63% Chlorogenic Acid Mg 200 2.63% Cyanidin 3-glucoside(Nanoformulated)^(1,2) Mg 400 5.26% Phloridzin Mg 200 2.63% Touchi Mg1000 13.16% Total Weight G 7.60 100.00%

TABLE 10C Composition Of A Mixture For Lowering The Risks Of Type-2Diabetes Disease - May Also Include Some Bioactive Compounds From TablesBefore & After This Table Unit +/−50% WT % Botanicals Cocciniacordifolia ⁺ Mg 200 3.03% Cordyceps sinensis ⁺ Mg 200 3.03% Green CoffeeBean Extract Mg 1200 18.18% Lamon Variety Borlotto Bean Extract Mg 2003.03% Momordica charantia ⁺ Mg 200 3.03% Salacia oblonga ⁺ Mg 800 12.12%Sorghum bicolor ⁺ Mg 1000 15.15% White Mulberry (Providing Mg 400 6.06%1-deoxynojirinmycin 15 (DNJ) mg) Extract Chemicals4-(4-Hydroxyphenyl)butan-2-one Mg 400 6.06% (Nanoformulated)^(1,2) BetaGlucan Mg 200 3.03% Chlorogenic Acid Mg 200 3.03% Cyanidin 3-glucoside(Nanoformulated)^(1,2) Mg 400 6.06% Phloridzin Mg 200 3.03% Touchi Mg1000 15.15% Total Weight G 6.60 100.00%

TABLE 10D Composition Of A Mixture For Lowering The Risks Of Type-2Diabetes Disease - May Also Include Some Bioactive Compounds From TablesBefore & After This Table Unit +/−50% WT % Botanicals Cocciniacordifolia ⁺ Mg 200 7.02% Emblica officinalis ⁺ Mg 200 7.02% GreenCoffee Bean Extract Mg 1200 42.11% Lagerstroemia speciosa ⁺ Mg 50 1.75%Punica granatum Mg 200 7.02% Syzygium cumini ⁺ Mg 200 7.02% Chemicals4-(4-Hydroxyphenyl)butan-2-one Mg 400 14.04% (Nanoformulated)^(1,2)Cyanidin 3-glucoside (Nanoformulated)^(1,2) Mg 400 14.04% Total Weight G2.85 100.00%

4-(4-Hydroxyphenyl)butan-2-one is raspberry ketone.

Green coffee bean extract has chlorogenic acid (CHA).

Explanation Of Notations {+, *, 1, 2, 3 and 4) + A component (meaning anextract or a powder or a bioactive compound or a bioactive molecule fromany part of the specific plant) * Found in Citrullus vulgaris ⁺ 1Nanoformulated means nanoemulsion/nanodispersion/nanosuspension ornanoencapsulation 2 Chemically coupled with Triphenylphosphonium (TPP)or a chemical derivative of Triphenylphosphonium or a structural analogof Triphenylphosphonium 3 Higher bioavailability with black pepper(Piper nigrum) and/or vitamin D₃ 4 FLLL-11 or FLLL-12 or GO-Y030 orGO-Y031 can replace curcumin

TABLE 11 Composition Of A Mixture Of Sugar Free Sweetener Unit +/−50% WT% Botanical Stevia rebaudiana ⁺ Mg 20 0.42% Chemicals Erythritol Mg 450095.34% Trehalose Mg 200 4.24% Total Weight G 4.72 100.00%

TABLE 12A Composition Of A Mixture Of Sugar Free Super-Sweetener Unit+/−50% WT % Botanicals Capparis masaikai ⁺ (Mabinlins Protein) Mg 50.11% Stevia rebaudiana ⁺ Mg 20 0.42% Chemicals Erythritol Mg 450095.24% Trehalose Mg 200 4.23% Total Weight G 4.72 100.00%

TABLE 12B Composition Of A Mixture Of Sugar Free Super-Sweetener Unit+/−50% WT % Botanicals Curculigo latifolia ⁺ (Curculin Protein) Mg 50.11% Stevia rebaudiana ⁺ Mg 20 0.42% Chemicals Erythritol Mg 450095.24% Trehalose Mg 200 4.23% Total Weight G 4.72 100.00%

TABLE 12C Composition Of A Mixture Of Sugar Free Super-Sweetener Unit+/−50% WT % Botanicals Dioscoreophyllum cumminsii ⁺ Mg 2 0.04% (MonellinProtein) Stevia rebaudiana ⁺ Mg 20 0.42% Chemicals Erythritol Mg 450095.30% Trehalose Mg 200 4.24% Total Weight G 4.72 100.00%

TABLE 12D Composition Of A Mixture Of Sugar Free Super-Sweetener Unit+/−50% WT % Botanicals Momordica grosvenorii/ Mg 5 0.11% Siraitiagrosvenorii ⁺ Stevia rebaudiana ⁺ Mg 20 0.42% Chemicals Erythritol Mg4500 95.24% Trehalose Mg 200 4.23% Total Weight G 4.72 100.00%

TABLE 12E Composition Of A Mixture Of Sugar Free Super-Sweetener Unit+/−50% WT % Botanicals Pentadiplandra brazzeana ⁺ Mg 5 0.11% (BrazzeinProtein) Pentadiplandra brazzeana ⁺ Mg 5 0.11% (Pentadin Protein) Steviarebaudiana ⁺ Mg 20 0.42% Chemicals Erythritol Mg 4500 95.14% TrehaloseMg 200 4.23% Total Weight G 4.73 100.00%

TABLE 12F Composition Of A Mixture Of Sugar Free Super-Sweetener Unit+/−50% WT % Botanicals Stevia rebaudiana ⁺ Mg 20 0.42% Synsepalumdulcificum ⁺ Mg 5 0.11% (Miraculin Protein) Chemicals Erythritol Mg 450095.24% Trehalose Mg 200 4.23% Total Weight G 4.72 100.00%

TABLE 12G Composition Of A Mixture Of Sugar Free Super-Sweetener Unit+/−50% WT % Botanicals Stevia rebaudiana ⁺ Mg 20 0.42% Thaumatococcusdaniellii ⁺ Mg 1 0.02% (Thaumatin Protein) Chemicals Erythritol Mg 450095.32% Trehalose Mg 200 4.24% Total Weight G 4.72 100.00%

TABLE 12H Composition Of A Mixture Of Sugar Free Super-Sweetener Unit+/−50% WT % Botanicals Dioscoreophyllum cumminsii ⁺ Mg 2 0.04% (MonellinProtein) Pentadiplandra brazzeana ⁺ Mg 5 0.11% (Brazzein Protein)Pentadiplandra brazzeana ⁺ Mg 5 0.11% (Pentadin Protein) Steviarebaudiana ⁺ Mg 20 0.42% Chemicals Erythritol Mg 4500 95.10% TrehaloseMg 200 4.23% Total Weight G 4.73 100.00%

TABLE 12I Composition Of A Mixture Of Sugar Free Super-Sweetener Unit+/−50% WT % Botanicals Dioscoreophyllum cumminsii ⁺ Mg 2 0.04% (MonellinProtein) Pentadiplandra brazzeana ⁺ Mg 5 0.11% (Brazzein Protein)Pentadiplandra brazzeana ⁺ Mg 5 0.11% (Pentadin Protein) Steviarebaudiana ⁺ Mg 20 0.42% Synsepalum dulcificum ⁺ Mg 5 0.11% (MiraculinProtein) Chemicals Erythritol Mg 4500 95.00% Trehalose Mg 200 4.22%Total Weight G 4.73 100.00%

TABLE 12J Composition Of A Mixture Of Sugar Free Super-Sweetener Unit+/−50% WT % Botanicals Capparis masaikai ⁺ Mg 5 0.11% (MabinlinsProtein) Dioscoreophyllum cumminsii ⁺ Mg 2 0.04% (Monellin Protein)Pentadiplandra brazzeana ⁺ Mg 5 0.11% (Brazzein Protein) Pentadiplandrabrazzeana ⁺ Mg 5 0.11% (Pentadin Protein) Stevia rebaudiana ⁺ Mg 200.42% Synsepalum dulcificum ⁺ Mg 5 0.11% (Miraculin Protein) ChemicalsErythritol Mg 4500 94.90% Trehalose Mg 200 4.22% Total Weight G 4.74100.00%

TABLE 12K Composition Of A Mixture Of Sugar Free Super-Sweetener Unit+/−50% WT % Botanicals Curculigo latifolia ⁺ Mg 5 0.11% (CurculinProtein) Dioscoreophyllum cumminsii ⁺ Mg 2 0.04% (Monellin Protein)Pentadiplandra brazzeana ⁺ Mg 5 0.11% (Brazzein Protein) Pentadiplandrabrazzeana ⁺ Mg 5 0.11% (Pentadin Protein) Stevia rebaudiana ⁺ Mg 200.42% Synsepalum dulcificum ⁺ Mg 5 0.11% (Miraculin Protein) ChemicalsErythritol Mg 4500 94.90% Trehalose Mg 200 4.22% Total Weight G 4.74100.00%

TABLE 12L Composition Of A Mixture Of Sugar Free Super-Sweetener Unit+/−50% WT % Botanicals Capparis masaikai ⁺ Mg 1 0.02% (MabinlinsProtein) Curculigo latifolia ⁺ Mg 1 0.02% (Curculin Protein)Dioscoreophyllum cumminsii ⁺ Mg 2 0.04% (Monellin Protein)Pentadiplandra brazzeana ⁺ Mg 5 0.11% (Brazzein Protein) Pentadiplandrabrazzeana ⁺ Mg 5 0.11% (Pentadin Protein) Stevia rebaudiana ⁺ Mg 200.42% Synsepalum dulcificum ⁺ Mg 5 0.11% (Miraculin Protein) ChemicalsErythritol Mg 4500 94.96% Trehalose Mg 200 4.22% Total Weight G 4.74100.00%

TABLE 12M Composition Of A Mixture Of Sugar Free Super-Sweetener Unit+/−50% WT % Botanicals Capparis masaikai ⁺ Mg 1 0.02% (MabinlinsProtein) Curculigo latifolia ⁺ Mg 1 0.02% (Curculin Protein)Dioscoreophyllum cumminsii ⁺ Mg 5 0.04% (Monellin Protein)Pentadiplandra brazzeana ⁺ Mg 5 0.11% (Brazzein Protein) Pentadiplandrabrazzeana ⁺ Mg 5 0.11% (Pentadin Protein) Stevia rebaudiana ⁺ Mg 200.42% Synsepalum dulcificum ⁺ Mg 5 0.11% (Miraculin Protein) ChemicalsErythritol Mg 4500 94.90% Trehalose Mg 200 4.22% Total Weight G 4.74100.00%

+ Means a component (meaning an extract or a powder or a bioactivecompound or a bioactive molecule from any part of the specific plant).

TABLE 13A Composition Of A Mixture Of A Chewable/Soluble Strip ForHealth Unit +/−50% WT % Chemicals Anhydrous Caffeine/Caffeine Mg 500.92% Curcumin/Nanoformulated Curcumin Mg 50 0.92% EpigallocatechinGallate Mg 50 0.92% Inositol Mg 12.5 0.23% L-Arginine Mg 4000 73.89%Licoricidin Mg 50 0.92% Licorisoflavan A Mg 50 0.92% Resveratrol Mg 500.92% Taurine Mg 50 0.92% Optional Botanicals Astragalus Root⁵ Mg 2003.69% Licorice Root Extract- Mg 200 3.69% Deglycyrrhizinated MagnoliaBark Extract Mg 50 0.92% Tea Leaf (Green) Extract Mg 50 0.92% VitaminsBiotin Mg 0.5 0.1% Folate Mg 0.5 0.1% Niacinimide Mg 200 3.69% VitaminB₁ Mg 25 0.46% Vitamin B₂ Mg 25 0.46% Vitamin B₃ Mg 25 0.46% Vitamin B₅Mg 50 0.92% Vitamin B₆ Mg 25 0.46% Vitamin B₁₂ Mg 0.01 0.00% Vitamin CMg 200 3.69% Vitamin D Mg 0.1 0.00 Other Streptococcus salivarius K12Billion 10 0.00% Total Weight G 5.41 100.00%

TABLE 13B Composition Of A Mixture Of A Chewable/Soluble Strip ForHealth Unit +/−50% WT % Chemicals Anhydrous Caffeine/Caffeine Mg 500.93% Epigallocatechin Gallate Mg 50 0.93% Inositol Mg 12.5 0.23%L-Arginine Mg 4000 74.58% Licoricidin Mg 50 0.93% Licorisoflavan A Mg 500.93% Resveratrol Mg 50 0.93% Taurine Mg 50 0.93% Optional BotanicalsAstragalus Root⁵ Mg 200 3.73% Licorice Root Extract- Mg 200 3.73%Deglycyrrhizinated Magnolia Bark Extract Mg 50 0.93% Tea Leaf (Green)Extract Mg 50 0.93% Vitamins Biotin Mg 0.5 0.01% Folate Mg 0.5 0.01%Niacinimide Mg 200 3.73% Vitamin B₁ Mg 25 0.47% Vitamin B₂ Mg 25 0.47%Vitamin B₃ Mg 25 0.47% Vitamin B₅ Mg 50 0.93% Vitamin B₆ Mg 25 0.47%Vitamin B₁₂ Mg 0.01 0.00% Vitamin C Mg 200 3.73% Vitamin D Mg 0.1 0.00%Other Streptococcus salivarius K12 Billion 10 0.00% Total Weight G 5.36100.00%

TABLE 13C Composition Of A Mixture Of A Chewable/Soluble Strip ForHealth Unit +/−50% WT % Chemicals Anhydrous Caffeine/Caffeine Mg 500.94% Inositol Mg 12.5 0.24% L-Arginine Mg 4000 75.28% Licoricidin Mg 500.94% Licorisoflavan A Mg 50 0.94% Resveratrol Mg 50 0.94% Taurine Mg 500.94% Optional Botanicals Astragalus Root⁵ Mg 200 3.76% Licorice RootExtract- Mg 200 3.76% Deglycyrrhizinated Magnolia Bark Extract Mg 500.94% Tea Leaf (Green) Extract Mg 50 0.94% Vitamins Biotin Mg 0.5 0.01%Folate Mg 0.5 0.01% Niacinimide Mg 200 3.76% Vitamin B₁ Mg 25 0.47%Vitamin B₂ Mg 25 0.47% Vitamin B₃ Mg 25 0.47% Vitamin B₅ Mg 50 0.94%Vitamin B₆ Mg 25 0.47% Vitamin B₁₂ Mg 0.01 0.00% Vitamin C Mg 200 3.76%Vitamin D Mg 0.1 0.00% Other Streptococcus salivarius K12 Billion 100.00% Total Weight G 5.31 100.00%

TABLE 13D Composition Of A Mixture Of A Chewable/Soluble Strip ForHealth Unit +/−50% WT % Chemicals Anhydrous Caffeine/Caffeine Mg 503.81% Inositol Mg 12.5 0.95% Licoricidin Mg 50 3.81% Licorisoflavan A Mg50 3.81% Resveratrol Mg 50 3.81% Taurine Mg 50 3.81% Optional BotanicalsAstragalus Root⁵ Mg 200 15.23% Licorice Root Extract- Mg 200 15.23%Deglycyrrhizinated Magnolia Bark Extract Mg 50 3.81% Tea Leaf (Green)Extract Mg 50 3.81% Vitamins Biotin Mg 0.5 0.04% Folate Mg 0.5 0.04%Niacinimide Mg 200 15.23% Vitamin B₁ Mg 25 1.90% Vitamin B₂ Mg 25 1.90%Vitamin B₃ Mg 25 1.90% Vitamin B₅ Mg 50 3.81% Vitamin B₆ Mg 25 1.90%Vitamin B₁₂ Mg 0.01 0.00% Vitamin C Mg 200 15.23% Vitamin D Mg 0.1 0.01%Other Streptococcus salivarius K12 Billion 10 0.00% Total Weight G 1.31100.00%

TABLE 13E Composition Of A Mixture Of A Chewable/Soluble Strip ForHealth Unit +/−50% WT % Chemicals Anhydrous Caffeine/Caffeine Mg 503.96% Inositol Mg 12.5 0.99% Licoricidin Mg 50 3.96% Licorisoflavan A Mg50 3.96% Taurine Mg 50 3.96% Optional Botanicals Astragalus Root⁵ Mg 20015.83% Licorice Root Extract-Deglycyrrhizinated Mg 200 15.83% MagnoliaBark Extract Mg 50 3.96% Tea Leaf (Green) Extract Mg 50 3.96% VitaminsBiotin Mg 0.5 0.04% Folate Mg 0.5 0.04% Niacinimide Mg 200 15.83%Vitamin B₁ Mg 25 1.98% Vitamin B₂ Mg 25 1.98% Vitamin B₃ Mg 25 1.98%Vitamin B₅ Mg 50 3.96% Vitamin B₆ Mg 25 1.98% Vitamin B₁₂ Mg 0.01 0.00%Vitamin C Mg 200 15.83% Vitamin D Mg 0.1 0.01% Other Streptococcussalivarius K12 Billion 10 0.00% Total Weight G 1.26 100.00%

TABLE 13F Composition Of A Mixture Of A Chewable/Soluble Strip ForHealth Unit +/−50% WT % Chemicals Anhydrous Caffeine/Caffeine Mg 504.70% Inositol Mg 12.5 1.18% Licoricidin Mg 50 4.70% Licorisoflavan A Mg50 4.70% Taurine Mg 50 4.70% Optional Botanicals Licorice RootExtract-Deglycyrrhizinated Mg 200 18.80% Magnolia Bark Extract Mg 504.70% Tea Leaf (Green) Extract Mg 50 4.70% Vitamins Biotin Mg 0.5 0.05%Folate Mg 0.5 0.05% Niacinimide Mg 200 18.80% Vitamin B₁ Mg 25 2.35%Vitamin B₂ Mg 25 2.35% Vitamin B₃ Mg 25 2.35% Vitamin B₅ Mg 50 4.70%Vitamin B₆ Mg 25 2.35% Vitamin B₁₂ Mg 0.01 0.00% Vitamin C Mg 200 18.80%Vitamin D Mg 0.1 0.01% Other Streptococcus salivarius K12 Billion 100.00% Total Weight G 1.06 100.00%

TABLE 13G Composition Of A Mixture Of A Chewable/Soluble Strip ForHealth Unit +/−50% WT % Chemicals Anhydrous Mg 50 5.79%Caffeine/Caffeine Inositol Mg 12.5 1.45% Licoricidin Mg 50 5.79%Licorisoflavan A Mg 50 5.79% Taurine Mg 50 5.79% Optional BotanicalsMagnolia Bark Extract Mg 50 5.79% Tea Leaf (Green) Extract Mg 50 5.79%Vitamins Biotin Mg 0.5 0.06% Folate Mg 0.5 0.06% Niacinimide Mg 20023.16% Vitamin B₁ Mg 25 2.89% Vitamin B₂ Mg 25 2.89% Vitamin B₃ Mg 252.89% Vitamin B₅ Mg 50 5.79% Vitamin B₆ Mg 25 2.89% Vitamin B₁₂ Mg 0.010.00% Vitamin C Mg 200 23.16% Vitamin D Mg 0.1 0.01% Other Streptococcussalivarius Billion 10 0.00% K12 Total Weight G 0.86 100.00%

TABLE 13H Composition Of A Mixture Of A Chewable/Soluble Strip ForHealth Unit +/−50% WT % Chemicals Anhydrous Mg 50 6.15%Caffeine/Caffeine Inositol Mg 12.5 1.54% Licoricidin Mg 50 6.15%Licorisoflavan A Mg 50 6.15% Taurine Mg 50 6.15% Optional Botanical TeaLeaf (Green) Extract Mg 50 6.15% Vitamins Biotin Mg 0.5 0.06% Folate Mg0.5 0.06% Niacinimide Mg 200 24.58% Vitamin B₁ Mg 25 3.07% Vitamin B₂ Mg25 3.07% Vitamin B₃ Mg 25 3.07% Vitamin B₅ Mg 50 6.15% Vitamin B₆ Mg 253.07% Vitamin B₁₂ Mg 0.01 0.00% Vitamin C Mg 200 24.58% Vitamin D Mg 0.10.01% Other Streptococcus salivarius Billion 10 0.00% K12 Total Weight G0.81 100.00%

TABLE 13I Composition Of A Mixture Of A Chewable/Soluble Strip ForHealth Unit +/−50% WT % Chemicals Anhydrous Caffeine/Caffeine Mg 506.55% Inositol Mg 12.5 1.64% Licoricidin Mg 50 6.55% Licorisoflavan A Mg50 6.55% Taurine Mg 50 6.55% Vitamins Biotin Mg 0.5 0.07% Folate Mg 0.50.07% Niacinimide Mg 200 26.19% Vitamin B₁ Mg 25 3.27% Vitamin B₂ Mg 253.27% Vitamin B₃ Mg 25 3.27% Vitamin B₅ Mg 50 6.55% Vitamin B₆ Mg 253.27% Vitamin B₁₂ Mg 0.01 0.00% Vitamin C Mg 200 26.19% Vitamin D Mg 0.10.01% Other Streptococcus salivarius K12 Billion 10 0.00% Total Weight G0.76 100.00%

TABLE 13J Composition Of A Mixture Of A Chewable/Soluble Strip ForHealth Unit +/−50% WT % Chemicals Anhydrous Caffeine/Caffeine Mg 506.55% Inositol Mg 12.5 1.64% Licoricidin Mg 50 6.55% Licorisoflavan A Mg50 6.55% Taurine Mg 50 6.55% Vitamins Folate Mg 0.5 0.07% Niacinimide Mg200 26.21% Vitamin B₁ Mg 25 3.28% Vitamin B₂ Mg 25 3.28% Vitamin B₃ Mg25 3.28% Vitamin B₅ Mg 50 6.55% Vitamin B₆ Mg 25 3.28% Vitamin B₁₂ Mg0.01 0.00% Vitamin C Mg 200 26.21% Vitamin D Mg 0.1 0.01% OtherStreptococcus salivarius K12 Billion 10 0.00% Total Weight G 0.76100.00%

TABLE 13K Composition Of A Mixture Of A Chewable/Soluble Strip ForHealth Unit +/−50% WT % Chemicals Anhydrous Caffeine/Caffeine Mg 506.56% Inositol Mg 12.5 1.64% Licoricidin Mg 50 6.56% Licorisoflavan A Mg50 6.56% Taurine Mg 50 6.56% Vitamins Niacinimide Mg 200 26.23% VitaminB₁ Mg 25 3.28% Vitamin B₂ Mg 25 3.28% Vitamin B₃ Mg 25 3.28% Vitamin B₅Mg 50 6.56% Vitamin B₆ Mg 25 3.28% Vitamin B₁₂ Mg 0.01 0.00% Vitamin CMg 200 26.23% Vitamin D Mg 0.1 0.01% Other Streptococcus salivarius K12Billion 10 0.00% Total Weight G 0.76 100.00%

TABLE 13L Composition Of A Mixture Of A Chewable/Soluble Strip ForHealth Unit +/−50% WT % Chemicals Anhydrous Caffeine/Caffeine Mg 508.89% Inositol Mg 12.5 2.22% Licoricidin Mg 50 8.89% Licorisoflavan A Mg50 8.89% Taurine Mg 50 8.89% Vitamins Vitamin B₁ Mg 25 4.44% Vitamin B₂Mg 25 4.44% Vitamin B₃ Mg 25 4.44% Vitamin B₅ Mg 50 8.89% Vitamin B₆ Mg25 4.44% Vitamin B₁₂ Mg 0.01 0.00% Vitamin C Mg 200 35.55% Vitamin D Mg0.1 0.02% Other Streptococcus salivarius K12 Billion 10 0.00% TotalWeight G 0.56 100.00%

TABLE 13M Composition Of A Mixture Of A Chewable/Soluble Strip ForHealth Unit +/−50% WT % Chemicals Anhydrous Caffeine/Caffeine Mg 509.30% Inositol Mg 12.5 2.33% Licoricidin Mg 50 9.30% Licorisoflavan A Mg50 9.30% Taurine Mg 50 9.30% Vitamins Vitamin B₂ Mg 25 4.65% Vitamin B₃Mg 25 4.65% Vitamin B₅ Mg 50 9.30% Vitamin B₆ Mg 25 4.65% Vitamin B₁₂ Mg0.01 0.00% Vitamin C Mg 200 37.20% Vitamin D Mg 0.1 0.02% OtherStreptococcus salivarius K12 Billion 10 0.00% Total Weight G 0.54100.00%

TABLE 13N Composition Of A Mixture Of A Chewable/Soluble Strip ForHealth Unit +/−50% WT % Chemicals Anhydrous Caffeine/Caffeine Mg 509.75% Inositol Mg 12.5 2.44% Licoricidin Mg 50 9.75% Licorisoflavan A Mg50 2.44% Taurine Mg 50 2.44% Vitamins Vitamin B₃ Mg 25 4.88% Vitamin B₅Mg 50 9.75% Vitamin B₆ Mg 25 4.88% Vitamin B₁₂ Mg 0.01 0.00% Vitamin CMg 200 39.02% Vitamin D Mg 0.1 0.02% Other Streptococcus salivarius K12Billion 10 0.00% Total Weight G 0.51 100.00%

TABLE 13O Composition Of A Mixture Of A Chewable/Soluble Strip ForHealth Unit +/−50% WT % Chemicals Anhydrous Caffeine/Caffeine Mg 5010.25% Inositol Mg 12.5 2.56% Licoricidin Mg 50 10.25% Licorisoflavan AMg 50 10.25% Taurine Mg 50 10.25% Vitamins Vitamin B₅ Mg 50 10.25%Vitamin B₆ Mg 25 5.13% Vitamin B₁₂ Mg 0.01 0.00% Vitamin C Mg 200 41.02%Vitamin D Mg 0.1 0.02% Other Streptococcus salivarius K12 Billion 100.00% Total Weight G 0.49 100.00%

TABLE 13P Composition Of A Mixture Of A Chewable/Soluble Strip ForHealth Unit +/−50% WT % Chemicals Anhydrous Caffeine/Caffeine Mg 5011.43% Inositol Mg 12.5 2.86% Licoricidin Mg 50 11.43% Licorisoflavan AMg 50 11.43% Taurine Mg 50 11.43% Vitamins Vitamin B₆ Mg 25 5.71%Vitamin B₁₂ Mg 0.01 0.00% Vitamin C Mg 200 45.70% Vitamin D Mg 0.1 0.02%Other Streptococcus salivarius K12 Billion 10 0.00% Total Weight G 0.44100.00%

TABLE 13Q Composition Of A Mixture Of A Chewable/Soluble Strip ForHealth Unit +/−50% WT % Chemicals Anhydrous Caffeine/Caffeine Mg 5012.12% Inositol Mg 12.5 3.03% Licoricidin Mg 50 12.12% Licorisoflavan AMg 50 12.12% Taurine Mg 50 12.12% Vitamins Vitamin B₁₂ Mg 0.01 0.00%Vitamin C Mg 200 48.47% Vitamin D Mg 0.1 0.02% Other Streptococcussalivarius K12 Billion 10 0.00% Total Weight G 0.41 100.00%

TABLE 13R Composition Of A Mixture Of A Chewable/Soluble Strip ForHealth Unit +/−50% WT % Chemicals Anhydrous Caffeine/Caffeine Mg 5012.12% Inositol Mg 12.5 3.03% Licoricidin Mg 50 12.12% Licorisoflavan AMg 50 12.12% Taurine Mg 50 12.12% Vitamins Vitamin C Mg 200 48.47%Vitamin D Mg 0.1 0.02% Other Streptococcus salivarius K12 Billion 100.00% Total Weight G 0.41 100.00%

TABLE 13S Composition Of A Mixture Of A Chewable/Soluble Strip ForHealth Unit +/−50% WT % Chemicals Anhydrous Caffeine/Caffeine Mg 5023.52% Inositol Mg 12.5 5.88% Licoricidin Mg 50 23.52% Licorisoflavan AMg 50 23.52% Taurine Mg 50 23.52% Vitamin Vitamin D Mg 0.1 0.05% OtherStreptococcus salivarius K12 Billion 10 0.00% Total Weight G 0.21100.00%

TABLE 13T Composition Of A Mixture Of A Chewable/Soluble Strip ForHealth Unit +/−50% WT % Chemicals Anhydrous Mg 50 23.53%Caffeine/Caffeine Inositol Mg 12.5 5.88% Licoricidin Mg 50 23.53%Licorisoflavan A Mg 50 23.53% Taurine Mg 50 23.53% Other Streptococcussalivarius Billion 10 0.00% K12 Total Weight G 0.21 100.00%

TABLE 13U Composition Of A Mixture Of A Chewable/Soluble Strip ForHealth Unit +/−50% WT % Chemicals Inositol Mg 12.5 7.69% Licoricidin Mg50 30.77% Licorisoflavan A Mg 50 30.77% Taurine Mg 50 30.77% OtherStreptococcus salivarius Billion 10 0.00% K12 Total Weight G 0.16100.00%

TABLE 13V Composition Of A Mixture Of A Chewable/Soluble Strip ForHealth Unit +/−50% WT % Chemicals Licoricidin Mg 50 33.33%Licorisoflavan A Mg 50 33.33% Taurine Mg 50 33.33% Other Streptococcussalivarius Billion 10 0.00% K12 Total Weight G 0.15 100.00%

TABLE 13W Composition Of A Mixture Of A Chewable/Soluble Strip ForHealth Unit +/−50% WT % Chemicals Licoricidin Mg 50 50.00%Licorisoflavan A Mg 50 50.00% Other Streptococcus salivarius Billion 100.00% K12 Total Weight G 0.10 100.00%

In formulations described in Table-13A through Table-13W, Licoricidinand Licorisoflavan A can prevent gum diseases. In formulations describedin Table-13A through Table-13W, propolis extract of about 100 mg can beadded. In formulations described in Table-13A through Table-13W, coffeeand D-Ribose can be added in about 1:1 weight ratio.

In formulations described in Table-13A through Table-13W, L-ArginineAlpha Keto-Glutarate (AAKG) (about 4 grams+/−50%) can be added insteadof L-Arginine. L-Arginine or L-Arginine Alpha Keto-Glutarate can beencapsulated in methocel, a micro-polymer hydrophilic ether matrix tocontrol the release rate of L-Arginine or L-Arginine AlphaKeto-Glutarate.

In formulations described in Table-13A through Table-13W, Astragalusroot⁵ can be mixed with about 200 mg extract of Agaricus subrufescens,about 200 mg extract of Cordyceps sinensis, about 200 mg extract ofGanoderma lucidum, about 200 mg extract of Grifola frondosa, about 200mg extract of Hericium erinaceus, about 200 mg extract of Phallusindusiatus and about 200 mg extract of Phellinus linteus.

In formulations described in Table-13A through Table-13W, about 200 mgof Commiphora myrrha powder can be added. In formulations described inTable-13A through Table-13W, about 200 mg of folic acid can be added.

In formulations described in Table-13A through Table-13W, about 200 mgof catalase, about 200 mg of glutathione peroxidase, about 1000 mg ofL-Methionine, about 200 mcg of selenium amino acid complex (sodiumselenite, L-selenomethionin and selenium-methyl L-selenocysteine) andabout 200 mg superoxide dismutase can be added.

In formulations described in Table-13A through Table-13W, about 200 mgof Emblica officinalis extract can be added.

In formulations described in Table-13A through Table-13W, about 1000 mgof D-Aspartic acid, 100 mg of 3-Beta-Hydroxy-Urs-12-En-28-Oic acid,about 100 mg of 2-Phenyl-Di-Benzyl-Benzopyran-4 One, about 200 mg ofextract of Cordyceps sinensis, about 400 mg of extract of Trigonellafoenum-graecum with about 50% testofen and about 200 mg of Panax ginsengcan be added.

In formulations described in Table-13A through Table-13W, inactiveingredients (malitol, sorbitol, gumbase, isomalt, calcium stearate,calcium pantothenate, flavor, gum Arabic, menthol, maltodextrin,acesulfame potassium, titanium dioxide, citric acid, malic acid,aspartame and glycerine) can be added.

TABLE 13X Composition Of A Mixture Of Probiotics - May Also Include SomeBioactive Compounds From Tables Before & After This Table Unit +/−50% WT% Chemicals Bovine Colostrum Mg 500 20.00% Lactoferrin Mg 2000 80.00%Probiotics Live Lactobacillus acidophilus Billion 10 0.00% LiveLactobacillus casei Billion 10 0.00% Live Lactobacillus GG Billion 200.00% Live Lactobacillus plantarum 299v Billion 10 0.00% LiveLactobacillus rhamnosus Billion 10 0.00% Other S. salivarius BLIS M18Billion 10 0.00% Total Weight G 2.50 100.00%

TABLE 13Y Composition Of A Mixture Of Chemicals, Vitamins & Minerals ToProtect Against Aging - May Also Include Some Bioactive Compounds FromTables Before & After This Table Unit +/−50% WT % Chemicals Alpha LipoicAcid Mg 200 2.07% Apoaequorin Mg 20 0.21% Beta-1,3 D Glucan Mg 600 6.20%Choline (Coganzin) Mg 200 2.07% Chrominum Mg 0.05 0.00% CoQ10 Mg 2002.07% Curcumin Mg 200 2.07% DHA Mg 400 4.14% Folic Acid Mg 1 0.01%Lactoferrin Mg 2000 20.68% L-Glutamine Mg 600 6.20% L-Theanin Mg 2002.07% L-Tyrosine Mg 600 6.20% Melatonine Mg 3 0.03% NicotinamideRiboside Mg 200 2.07% N-Acetyl-L-Cysteine Mg 800 8.27% N-AcetylGlucosamine Mg 800 8.27% N-Acetyl-L-Carnitine Mg 800 8.27%Phosphatidylserine Mg 200 2.07% Pterostilbene Mg 200 2.07% Quercetin Mg200 2.07% Resveratrol Mg 200 2.07% Ubiquinol Mg 200 2.07% VitaminsVitamin B12 Mg 1 0.01% Vitamin C Mg 600 6.20% Vitamin D3 Mg 0.25 0.00%Vitamin E Mg 200 2.07% Vitamin H Mg 0.1 0.00% Mineral & Others SeleniumMg 0.02 0.00% Vanadyl Sulfate Mg 5 0.05% Zinc Sulpfate Mg 40 0.41% TotalWeight G 9.70 100.00%

TABLE 13Z1 Composition Of A Mixture Of Chemicals, Vitamins & Minerals ToProtect Against Aging - May Also Include Some Bioactive Compounds FromTables Before & After This Table Unit +/−50% WT % Chemicals Alpha LipoicAcid Mg 200 2.11% Apoaequorin Mg 20 0.21% Beta-1,3 D Glucan Mg 600 6.34%Choline (Coganzin) Mg 200 2.11% Chrominum Mg 0.05 0.00% CoQ10 Mg 2002.11% Curcumin Mg 200 2.11% DHA Mg 400 4.23% Folic Acid Mg 1 0.01%Lactoferrin Mg 2000 21.13% L-Glutamine Mg 600 6.34% L-Tyrosine Mg 6006.34% Nicotinamide Riboside Mg 200 2.11% N-Acetyl-L-Cysteine Mg 8008.45% N-Acetyl Glucosamine Mg 800 8.45% N-Acetyl-L-Carnitine Mg 8008.45% Phosphatidylserine Mg 200 2.11% Pterostilbene Mg 200 2.11%Quercetin Mg 200 2.11% Resveratrol Mg 200 2.11% Ubiquinol Mg 200 2.11%Vitamins Vitamin B12 Mg 1 0.01% Vitamin C Mg 600 6.34% Vitamin D3 Mg0.25 0.00% Vitamin E Mg 200 2.11% Vitamin H Mg 0.1 0.00% Mineral &Others Selenium Mg 0.02 0.00% Vanadyl Sulfate Mg 5 0.05% Zinc SulpfateMg 40 0.42% Total Weight G 9.50 100.00%

TABLE 13Z2 Composition Of A Mixture Of Chemicals To Protect AgainstAging - May Also Include Some Bioactive Compounds From Tables Before &After This Table Chemicals Unit +/−50% WT % Withaferin A (Or A ChemicalDerivative/ Mg 400 33.33% Structural Analog Of Withaferin A)Nicotinamide Riboside Mg 200 16.66% Phosphatidylserine Mg 200 16.66%Quercetin Mg 200 16.66% Resveratrol Mg 200 16.66% Total Weight G 1.20100.00%

TABLE 13Z3 Composition Of A Mixture Of Chemicals To Protect AgainstAging - May Also Include Some Bioactive Compounds From Tables Before &After This Table Chemicals Unit +/−50% WT % Withaferin A (Or A ChemicalMg 400 40.00% Derivative/Structural Analog Of Withaferin A) NicotinamideRiboside Mg 200 20.00% Phosphatidylserine Mg 200 20.00% Quercetin Mg 20020.00% Total Weight G 1.00 100.00%

TABLE 13Z4 Composition Of A Mixture Of Chemicals To Protect AgainstAging - May Also Include Some Bioactive Compounds From Tables Before &After This Table Chemicals Unit +/−50% WT % Nicotinamide Riboside Mg 40040.00% Phosphatidylserine Mg 400 40.00% Quercetin Mg 200 20.00% TotalWeight G 1.00 100.00%

It should be noted that Nicotinamide Mononucleotide (NMN), aNicotinamide Adenine Dinucleotide precursor can replace NicotinamideRiboside. Nicotinamide Mononucleotide can also be nanoformulated.

Nanoemulsion/Nanodispersion/Nanosuspension

An oil dissolved bioactive compound 100 (e.g., curcumin in coconut oil)and an anti-solvent (e.g., water) are individually pressurized tocollide head on at an extremely high velocity to formnanoemulsion/nanodispersion/nanosuspension of the (oil dissolved)bioactive compounds 100 (in the anti-solvent).

Furthermore, nanoparticles of the bioactive compounds 100 can berealized after evaporating the anti-solvent ofnanoemulsion/nanodispersion/nanosuspension.

Furthermore, nanoemulsion/nanodispersion/nanosuspension/nanoparticle canenhance the efficacy and/or bioavailability of the bioactive compounds100 at a lower concentration.

Targeted Delivery: Nanoencapsulation

FIG. 6A illustrates a bioactive compound 100 and a bioactive molecule100A respectively.

FIG. 6B illustrates the bioactive compound 100 and bioactive molecule100A, which are encapsulated/caged in a nanoshell 120.

The size of the nanoshell 120 is about 25 nanometers to 115 nanometersin diameter and generally spherical in shape.

The nanoshell 120 can be biodegradable and less toxic.

By way of an example and not by way of any limitation, the nanoshell 120can be a boron nitride nanotube, carbon nanotube, Cornell-dot, cubisome,dendrimer (including plant based dendrimer), deoxyribonucleic acid (DNA)origami nanostructure, exosome, fullerene C₆₀ (e.g., malonic acidderivative of C₆₀), gold nanoparticles (suitably coated),grapefruit-derived nanovector (GNV), hollow magnetic cage molecule(e.g., Co₁₂C₆, Mn₁₂C₆ and Mn₂₄C₁₈), iron nanoparticle, lipidoid,liposome, mesoporous silica, micelle, nanocrystal, niosome, polysebacicacid (PSA), polysilsesquioxane (PSQ), porous silicon photonic crystal,quantum dot, quantum dot capped with glutathione, ribonucleic acid (RNA)origami nanostructure, self-assembling peptide (or self-assemblingprotein), silk-fibroin nanoparticle, solid-lipid nanoparticle, sphericalnucleic acid (SNA), synthasome, tubular/tetrahedral structurefabricated/constructed, utilizing DNA/RNA origami process, virus (e.g.,tobacco mosaic virus), zein-plant protein and zeolite-1-nanocrystal.

A Cornell-dot consists of dye molecules encased in a chemically inertsilica shell of about 5 nanometers in diameter.

Exosome contains RNAs. Cells communicate with each other by sending andreceiving exosomes—thus an exosome can be viewed as a unit forcell-to-cell biological communication directly by surface expressedligands or transferring molecules from the originating cells. Forexample, exosomes can carry material from the originating cancer cellsto suppress the immune system and stimulate angiogenesis for the growthof cancer cells. Recipient cells act, utilizing RNAs—for example,protein manufacturing in the case of messenger RNA or repression of theexpression of some genes in the case of microRNAs. Thus, exosomes (intheir specific pathways) can be utilized as the nanoshell 120 to deliverRNA (e.g., a specific small interfering RNA) for therapeutic purposes.

Furthermore, an MRI contrast agent and/or molecular tag can beencapsulated/caged in the nanoshell 120—thus realizing a multifunctionalnanoshell 120.

Monolayer coatings applied on the surface of gold nanoparticles canconsist of a mix of hydrophobic and hydrophilic layers. Furthermore,additional functionalization (with ligand(s)) on the surface of goldnanoparticles can be applied to target a selective cell type. Amechanism allows gold nanoparticles to pass through a cell membrane andthen seals the opening of the cell membrane, as soon as the goldnanoparticles enter into the selective cells. Harnessing of thiscell-penetrating mechanism of suitably functionalized gold nanoparticlescan be utilized as a way of delivering the bioactive compounds 100and/or bioactive molecules 100A and/or biosensing molecules to theselective cell's interior, by binding the bioactive compounds 100 and/orbioactive molecules 100A and/or biosensing molecules with a monolayer ofcoating and/or additional functionalization. The biosensing moleculescan detect/monitor a biomarker(s) to indicate an onset/decline of adisease.

Furthermore, the biosensing molecules can be embedded/integrated withina biodissolvable electronic circuit, which is generallyfabricated/constructed by silicon nanowires and/or silk nanowires.

By way of an example and not by way of any limitation, the nanoshell 120can be a combination of an artificial material and a biologicalmaterial.

By way of an example and not by way of any limitation, the nanoshell120, as a combination of an artificial inorganic/organic material and anatural biological material can be printed by three-dimensionalself-assembly/nano-printing or four-dimensional (4-D)self-assembly/nano-printing, wherein an extra dimension of time infour-dimensional self-assembly/nano-printing may allow the nanoshell 120to adapt/evolve/transform over time by an internal/external condition(e.g., pH and light).

Furthermore, a micelle can be fabricated/constructed, utilizing anaptamer, casein protein, epigallocatechin-3-O-gallate derivative (withvitamin E at the center of epigallocatechin-3-O-gallate derivative) andpolymer.

By way of an example and not by way of any limitation, the nanocrystalcan be a nanodiamond or nanohydroxyapatite. Hydroxyapatite is a form ofcalcium phosphate Ca₁₀(PO₄)₆(OH)₂.

Spherical nucleic acids are configured as a three-dimensionalsuperlattice assembly on an inorganic nanoparticle (typically gold orsilver). These three-dimensional superlattices can consist offunctionalized and oriented nucleic acids-attached to the inorganicnanoparticle. Spherical nucleic acids can be core-filled with the aboveinorganic nanoparticle or core-less without the above inorganicnanoparticle. The strength/length of the programmable DNA bonds withinthe three-dimensional superlattice assembly can be adjusted by varying aDNA sequence and sequence length. The properties of spherical nucleicacids can be adjusted by varying nanoparticle size, shape andcomposition.

Linear nucleic acids cannot enter into cells, but spherical nucleicacids can enter into cells. Core-less spherical nucleic acids do nottrigger an immune response. Thus, resulting in longer lifetime in ahuman body. Spherical nucleic acids can also cross a human body'sblood-brain barrier and skin. Spherical nucleic acids can enable nucleicacid based and small interfering RNA based therapeutics. A DNA sequencecan be matched to target genes for a different disease.

Synthasome is a spherical hollow nanoshell and it contains an aqueoussolution for protecting the bioactive compounds 100 and/or bioactivemolecules 100A. The synthasome has a nano-scaled channel(s) (e.g., atransmembrane protein channel) to permit or deny transport of thebioactive compounds 100 and/or bioactive molecules 100A across thesynthasome membrane.

Furthermore, an appropriate synthetic polymer material can be utilizedto customize the characteristics (e.g., control permeability, releaserate and stability) of the synthasome membrane.

Furthermore, a specialized biodegradable and non-toxic theranostic(e.g., perfluorocarbon based polymer) based on as the nanoshell 120 canspontaneously form itself out of tailored polymers macromolecules.

The formation requires a balance between the polymers macromolecules'hydrophilic (capable of dissolving in water) and hydrophobic (notdissolvable in water) parts. The hydrophobic portion makes it possibleto fill the nanoshell 120 with the bioactive compounds 100 and/orbioactive molecules 100A.

A relatively high concentration of the natural isotope 19F (fluorine)can make the theranostic nanoshell 120 clearly visible on highresolution images taken by magnetic resonance imaging. It is possible toobtain information about how the bioactive compounds 100 and/orbioactive molecules 100A are taken up by the cell and whether thetreatment, utilizing the bioactive compounds 100 and/or bioactivemolecules 100A are working or not.

Virus (e.g., Influenza A virus-IAV)-configured asharmless/non-infectious can act as a nanoshell 120. For example,Influenza A virus-IAV has eight (8) viral segments, encoding ten (10)major proteins. By eliminating two (2) viral segments, Influenza Avirus-IAV can be made harmless/non-infectious. Thus, Influenza Avirus-IAV as a nanoshell 120 can deliver the bioactive compounds 100and/or bioactive molecules 100A.

Furthermore, Influenza A virus-IAV can also deliver either coding RNAsor noncoding RNAs or micro RNAs to treat a specific disease.

The interior surface of the nanoshell 120 can be electrically charged(e.g., an opposite electrical charge polarity with respect to theelectrical charge polarity of the bioactive compounds 100 and/orbioactive molecules 100A to be encapsulated/caged in the nanoshell 120)to increase the encapsulation efficiency of the bioactive compounds 100and/or bioactive molecules 100A.

The exterior surface of the nanoshell 120 can be electrically charged toincrease the delivery efficiency of the bioactive compounds 100 and/orbioactive molecules 100A.

FIG. 6C illustrates the surface of the nanoshell 120, which can becoated with an optional protective (to protect from a human body'sblood/biological fluid) functional surface 140.

By way of an example and not by way of any limitation, a biologicalfluid can generally mean blood plasma, blood serum, cerebrospinal fluid,saliva, tear and urine.

The optional protective functional surface 140 can befabricated/constructed, utilizing a casein protein.

Optionally, the nanoshell 120 can be coated with an immune shielding (toprotect from a human body's inherent immune surveillance) functionalsurface 180.

The nanoshell 120 can be coated with galactosamine sugar molecules.

The nanoshell 120 can be coated with mannose sugar molecules.

The nanoshell 120 can be coated with folic acid molecules.

Both galactosamine sugar and mannose sugar can accumulate selectively inthe liver.

FIG. 6D illustrates the nanoshell 120, which can be furtherencapsulated/caged in a nanocarrier (e.g., an artificial cell,capsosome, DNA/RNA origami nanostructure, natural biopolymer chitosanand polyethylene glycol (PEG)) 160.

The DNA/RNA origami structure (nanostructure) with a lid that can staylocked until exposed to a DNA based key. The DNA/RNA origami structure(nanostructure) assembled with a lid which can be opened by a DNA/RNAstrand displacement/chemical coupling with a specific functionalizedoligonucleotide key (to chemically couple with a complementaryoligonucleotide or external stimulus). The DNA/RNA origami structure(nanostructure) can offer unprecedented control over shape, size,mechanical flexibility and surface modification. The surfaces of theDNA/RNA origami structure (nanostructure) assembled with a lid can befully addressable, allowing for the incorporation of multipleligands/labels to chemically bind with a biomarker(s) for the detectionof a disease(s) and delivery of bioactive compound(s)/molecule(s). Forexample, a DNA/RNA origami superstructure can include/integrate acluster of many DNA/RNA origami structures (nanostructures), eachDNA/RNA origami structure encapsulated/caged with its bioactivecompound(s)/molecule(s) and programmed set of inputs(s) for the deliveryof the bioactive compound(s)/molecule(s).

Furthermore, multiple inputs to the DNA/RNA origami structure(nanostructure) can be controlled by a basic principle of DNA/RNAcomputing (e.g., AND or NOR function) for the specific and simultaneousdetection of the disease(s) and the controlled delivery of the bioactivecompound(s)/molecule(s).

By way of an example and not by way of any limitation, utilizing ahybridization chain reaction, wherein cancer cells can be transfectedwith RNA transducers to recognize specific cancerous markers and inducePKR-mediated cancel cell death. Utilizing a cascade series of dynamicstructures (e.g., metastable DNA hairpin motifs/DNAzymes/entropy drivenstrand displacement) to create DNA based molecular circuitries forpoint-of-care diagnosis. The magnitude and duration of the multipleinputs to the DNA/RNA origami structure (nanostructure) can also beprogrammed from a continuous delivery mode of the bioactivecompound(s)/molecule(s) to a threshold-controlled delivery mode ofbioactive compound(s)/molecule(s).

In addition to its well-known DNA's structural properties-A only bindsT, G only binds C, one can predict the atomic-level structure ofvirtually any DNA origami nanostructure with remarkable accuracy.

Furthermore, because complementary DNA sequences recognize each other,short DNA strand can act as an accurate address label to direct a DNAorigami structure to a specified cell location.

Furthermore, a DNA based sensor within the nanoshell 120 can recognizean RNA message produced because of a certain biological event—thus cantrigger a release of RNA or DNA strands with therapeutic properties.

The size of the nanocarrier 160 is about 200 nanometers to 300nanometers in diameter and generally spherical in shape.

The nanocarrier 160 can be biodegradable and less toxic.

To construct a capsosome, a polymer film (containing building blocksmodified with cholesterol) is deposited onto small silica spheres.Liposomes (with an immune shielding functional surface 180) are anchoredto the cholesterol. Subsequently, more polymer films are added andcross-linked by disulfide bridges. Finally, the small silica spheres areetched away.

FIG. 6E illustrates the nanocarrier 160, which can be coated with theoptional protective (to protect from a human body's blood/biologicalfluid) functional surface 140.

The nanocarrier 160 can be coated with an immune shielding (to protectfrom a human body's inherent immune surveillance) functional surface180.

A human body's natural red blood/artificial red blood cell membrane canbe utilized as an immune shielding functional surface 180.

Ligands and/or receptors or native lipids and/or proteins of purified &active leukocytes (from a human body's white blood cells) can be alsoutilized as an immune shielding functional surface 180

A polymer membrane (e.g., polyethylene glycol polymer/water-likepolymer) can also be utilized as an immune shielding functional surface180 instead of a human body's red blood cell membrane, or ligands and/orreceptors or native lipids and/or proteins of purified & activeleukocytes (from a human body's white blood cells).

Polyethylene glycol membrane is a low-toxicity polymer and it can alsoshield against hydrophobic and/or electrostatic interactions.

However, a human body's natural red blood/artificial red blood can beutilized as an immune shielding functional surface 180, along with(including) a polymer membrane.

However, ligands and/or receptors or native lipids and/or proteins ofpurified & active leukocytes (from a human body's white blood cells) canbe utilized as an immune shielding functional surface 180, along with(including) a polymer membrane.

The extracellular space of a human brain is viscous and the viscositycan impede propagation of the nanoshell 120 in a human brain.

Considering the passage through a human body's blood-brain barrier andviscosity in the extracellular space of a human brain, a suitablediameter for propagation is estimated between 65 nanometers to 115nanometers.

Thus, only the nanoshell 120 (without the nanocarrier 160) can besuitable for the passage through a human body's blood-brain barrier andextracellular space of a human brain.

Biological receptors 240 are located on cell 260 of tissue 280.

A first targeting ligand 200 (e.g., cobalamin/vitamin) canrecognize/match/bind with specific biological receptors 240A of 240,located on cell 260 of tissue 280.

A second targeting ligand 220 (e.g., a specific antibody/aptamer) canrecognize/match/bind with specific biological receptors 240B of 240,located on cell 260 of tissue 280.

Both targeting ligands 200 and 220 can be utilized as dual navigatorstoward the biological receptors 240A and 240B respectively.

Both the nanocarrier 160 and nanoshell 120 can break, when (a) the firsttargeting ligand 200 recognizes/matches/binds with the specificbiological receptors 240A and (b) the second targeting ligand 220recognizes/matches/binds with the specific biological receptors 240B.

Alternatively, both the nanocarrier 160 and nanoshell 120 can breakunder an external condition/response (e.g., pH and light).

Thus, the bioactive compounds 100 and/or bioactive molecules 100A can bedelivered from the nanoshell 120 to the cell 260.

Example Applications of a Nanoshell (can be Decorated with a HumanBody's Red Blood Cell Membrane & Polyethylene Glycol Membrane)with/without a Nanocarrier (can be Decorated with a Human Body's RedBlood Cell Membrane & Polyethylene Glycol Membrane)

Molecular Coupling/Reprogramming

The nanoshell 120 can be encapsulated/caged in the nanocarrier 160. Thenanocarrier 160 can be decorated with the first targeting ligand 200.The first targeting ligand 200 can recognize/match/bind with specificbiological receptors 240A on the cell 260 to allow the nanoshell 120 tothe cell 260.

The nanoshell 120 can be decorated with a second targeting ligand 220Afor recognition of a nuclear pore and a third targeting ligand 220B(e.g., a messenger RNA aptamer). Upon passing through the nuclear pore,utilizing the second targeting ligand 220A that recognizes/matches/bindswith the nuclear pore, the nanoshell 120 can be uncapped in the nucleusof the cell 260 itself, when the third targeting ligand 220Brecognizes/matches/binds with a specific RNA (e.g., a messenger RNA).

The bioactive compounds 100 and/or bioactive molecules 100A can bedelivered from the nanoshell 120 specifically to couple and/or editand/or modulate the specific RNA (e.g., a messenger RNA)—thus enablingmolecular coupling/reprogramming for specific disease prevention.

However, for a specific application of molecular coupling/reprogramming,only the nanoshell 120 (without the nanocarrier 160) can also beutilized.

Gene Text Editing by Zinc Fingers, a Class of DNA-Binding Proteins

A human genome has about 3 billion pairs of the chemical letters A, C,G, and T (adenine, cytosine, guanine, and thymine). Now to 3 billionletters for a single appearance of the word “CAT,” and then replace a“C” with “T” to make the word “TAT.” To enable this, one needs an enzymethat is both capable of precise recognition of a specific DNA sequenceand outfitted with a scissor and paste to modify the chemical letters.One big unknown of the copy-paste editing strategy is any off-targeteffects that occur during fixing a defective or target gene, while itmust not damage another gene.

Most gene therapy techniques use a virus to carry new genes into a cell,but cannot direct the virus to insert genes into a specific site.

But zinc fingers are a class of engineered DNA-binding proteins used byliving cells to turn genes on and off. Each zinc finger recognizes a setof three letters, or bases, on the DNA molecule. Because the zincfingers recognize specific sequences of DNA, they guide the controlproteins to a specific site wherein the target gene begins. Thus, thezinc fingers can be utilized as a word processing system for cutting andpasting into a genetic text.

The nanoshell 120 can be encapsulated/caged in the nanocarrier 160. Thenanocarrier 160 can be decorated with the first targeting ligand 200.The first targeting ligand 200 can recognize/match/bind with specificbiological receptors 240A on the cell 260 to allow the nanoshell 120 tothe cell 260.

The nanoshell 120 can be decorated with a second targeting ligand 220Afor recognition of a nuclear pore and a third targeting ligand 220B.Upon passing through the nuclear pore, utilizing the second targetingligand 220A that recognizes/matches/binds with the nuclear pore, thenanoshell 120 can be uncapped in the nucleus of the cell 260, when thethird targeting ligand 220B recognizes/matches/binds with a specificDNA.

The zinc fingers (with desired DNA template) can be delivered from thenanoshell 120 specifically to edit a specific gene for specific diseaseprevention.

Furthermore, the zinc fingers (with a desired DNA template) can bedelivered from the nanoshell 120 specifically to genetically correctstem cells, prior to any use. This strategy can be used to generategenetically corrected, patient derived cells that could be transplantedwithout fear of a human body's immune-rejection.

However, for a specific application of genetic text editing, only thenanoshell 120 (without the nanocarrier 160) can also be utilized.

Gene Text Editing by Transcription Activator Like Effector Nucleases(TALENs)

The zinc fingers can snip away from a target site—thus, it may be apotentially serious safety problem.

Unlike the zinc fingers that bind to a group of three base pairs, TALENscan bind to individual nucleotides.

The nanoshell 120 can be encapsulated/caged in the nanocarrier 160. Thenanocarrier 160 can be decorated with the first targeting ligand 200.The first targeting ligand 200 can recognize/match/bind with specificbiological receptors 240A on the cell 260 to allow the nanoshell 120 tothe cell 260.

The nanoshell 120 can be decorated with a second targeting ligand 220Afor recognition of a nuclear pore and a third targeting ligand 220B.Upon passing through the nuclear pore, utilizing the second targetingligand 220A that recognizes/matches/binds with the nuclear pore, thenanoshell 120 can be uncapped in the nucleus of the cell 260, when thethird targeting ligand 220B recognizes/matches/binds with a specificDNA.

Transcription activator like effector nucleases (with desired DNAtemplate) can be delivered from the nanoshell 120 specifically to edit aspecific gene for specific disease prevention.

Furthermore, transcription activator like effector nucleases (with adesired DNA template) can be delivered from the nanoshell 120specifically to genetically correct stem cells, prior to any use. Thisstrategy can be used to generate genetically corrected, patient derivedcells that could be transplanted without fear of a human body'simmune-rejection.

However, for a specific application of genetic text editing, only thenanoshell 120 (without the nanocarrier 160) can also be utilized.

Gene Text Editing by a Synthetic RNA

Challenges of zinc finger or TALEN nucleases are getting a high level ofexpression and persistence of the introduced DNA construct.

A synthetic RNA that encodes a gene-editing protein (e.g., transcriptionactivator like effector nucleases) can be targeted to a specific gene.

The nanoshell 120 can be encapsulated/caged in the nanocarrier 160. Thenanocarrier 160 can be decorated with the first targeting ligand 200.The first targeting ligand 200 can recognize/match/bind with specificbiological receptors 240A on the cell 260 to allow the nanoshell 120 tothe cell 260.

The nanoshell 120 can be decorated with a second targeting ligand 220Afor recognition of a nuclear pore and a third targeting ligand 220B.Upon passing through the nuclear pore, utilizing the second targetingligand 220A that recognizes/matches/binds with the nuclear pore, thenanoshell 120 can be uncapped in the nucleus of the cell 260, when thethird targeting ligand 220B recognizes/matches/binds with a specificDNA.

A synthetic RNA to encode a gene-editing protein (e.g., transcriptionactivator like effector nucleases) (with desired DNA template) can bedelivered from the nanoshell 120 specifically to edit a specific genefor specific disease prevention.

Furthermore, a synthetic RNA to encode a gene-editing protein (e.g.,TALENs) (with a desired DNA template) can be delivered from thenanoshell 120 specifically to genetically correct stem cells, prior toany use. This strategy can be used to generate genetically corrected,patient derived stem cells that could be transplanted without fear of ahuman body's immune-rejection.

However, for a specific application of genetic text editing, only thenanoshell 120 (without the nanocarrier 160) can also be utilized.

Gene Text Editing by Cas9 Complexes with RNA

A DNA-cutting enzyme namely Cas9 complexed with a short 20-nucleotidesegment of RNA (matching the target DNA segment) can be programmed totarget a DNA sequence. Rather using a protein to target the desired DNAsequence, it uses RNA to guide the DNA-cutting enzyme namely Cas9 to thetargeted the DNA sequence. This takes advantage of the natural pairingof RNA and DNA sequences. In order to recognize the target DNA, Cas9requires the short sequence of “GG” in the target DNA adjacent to thesite bound by the targeting RNA. The DNA-cutting enzyme namely Cas9 doesnot have to change for every DNA sequence to be targeted—one has toreprogram it with a different RNA transcript, which is easy to designand implement.

The nanoshell 120 (encapsulating/caging CRISPR-Cas9 system) can beencapsulated/caged in the nanocarrier 160. The nanocarrier 160 can bedecorated with the first targeting ligand 200. The first targetingligand 200 can recognize/match/bind with specific biological receptors240A on the cell 260 to deliver the nanoshell 120 (encapsulating/cagingCRISPR-Cas9 system) to the cell 260.

Alternatively, the nanoshell 120 (encapsulating/caging CRISPR-Cas9system) can be decorated with a second targeting ligand 220A torecognize a nuclear pore. Upon passing through the nuclear pore,utilizing the second targeting ligand 220A that recognizes/matches/bindswith the nuclear pore, the nanoshell 120 can be uncapped in the nucleusof the cell 260 to deliver CRISPR-Cas9 system for gene editing. Thesecond targeting ligand 220A can be a molecule also.

Alternatively, the nanoshell 120 (encapsulating/caging CRISPR-Cas9system) can be decorated with the second targeting ligand 220A torecognize a nuclear pore and a third targeting ligand 220B. Upon passingthrough the nuclear pore, utilizing the second targeting ligand 220Athat recognizes/matches/binds with the nuclear pore, the nanoshell 120can be uncapped in the nucleus of the cell 260 to deliver CRISPR-Cas9system preciously for gene editing, when the third targeting ligand 220Brecognizes/matches/binds with a specific DNA. The third targeting ligand220B can be a molecule also.

However, just the nanoshell 120 (encapsulating/caging CRISPR-Cas9system) can be decorated with the first targeting ligand 200 torecognize/match/bind with specific biological receptors 240A on the cell260 to deliver CRISPR-Cas9 system.

Alternatively, just the nanoshell 120 (encapsulating/caging CRISPR-Cas9system) can be decorated with the first targeting ligand 200 torecognize/match/bind with specific biological receptors 240A on the cell260, the second targeting ligand 220A to recognize a nuclear pore. Uponpassing through the nuclear pore, utilizing the second targeting ligand220A that recognizes/matches/binds with the nuclear pore, the nanoshell120 can be uncapped in the nucleus of the cell 260 to deliverCRISPR-Cas9 system for gene editing.

Alternatively, just the nanoshell 120 (encapsulating/caging CRISPR-Cas9system) can be decorated with the first targeting ligand 200 torecognize/match/bind with specific biological receptors 240A on the cell260, the second targeting ligand 220A to recognize a nuclear pore andthe third targeting ligand 220B. Upon passing through the nuclear pore,utilizing the second targeting ligand 220A that recognizes/matches/bindswith the nuclear pore, the nanoshell 120 can be uncapped in the nucleusof the cell 260 to deliver CRISPR-Cas9 system precisely for geneediting, when the third targeting ligand 220B recognizes/matches/bindswith a specific DNA.

Alternatively, just the nanoshell 120 (in particular DNA/RNA origamistructure (nanostructure) encapsulating/caging CRISPR-Cas9 system) canbe decorated with the first targeting ligand 200 to recognize/match/bindwith specific biological receptors 240A on the cell 260 to deliverCRISPR-Cas9 system.

Thus, CRISPR-Cas9 system delivered via the nanoshell 120, decorated withthe targeting ligand 200 to recognize/match/bind with specificbiological receptors 240A on cancer cells can be utilized to cut/edit amutated DNA(s) causing cancer.

Similarly, CRISPR-Cas9 system delivered via the nanoshell 120, decoratedwith the targeting ligand 200 to recognize/match/bind with specificbiological receptors 240A on HIV-infected cells can be utilized tocut/edit HIV DNA.

Alternatively, just the nanoshell 120 (in particular DNA/RNA origamistructure (nanostructure) encapsulating/caging CRISPR-Cas9 system) canbe decorated with the first targeting ligand 200 to recognize/match/bindwith specific biological receptors 240A on the cell 260, the secondtargeting ligand 220A to recognize a nuclear pore. Upon passing throughthe nuclear pore, utilizing the second targeting ligand 220A thatrecognizes/matches/binds with the nuclear pore, the nanoshell 120 can beuncapped in the nucleus of the cell 260 to deliver CRISPR-Cas9 systemfor gene editing.

Alternatively, just the nanoshell 120 (in particular DNA/RNA origamistructure (nanostructure) encapsulating/caging CRISPR-Cas9 system) canbe decorated with the first targeting ligand 200 to recognize/match/bindwith specific biological receptors 240A on the cell 260, the secondtargeting ligand 220A to recognize a nuclear pore and the thirdtargeting ligand 220B. Upon passing through the nuclear pore, utilizingthe second targeting ligand 220A that recognizes/matches/binds with thenuclear pore, the nanoshell 120 can be uncapped in the nucleus of thecell 260 to deliver CRISPR-Cas9 system precisely for gene editing, whenthe third targeting ligand 220B recognizes/matches/binds with a specificDNA.

The engineered CRISPR-Cas9 system with RNA can be delivered from thenanoshell 120 specifically to activate or repress gene expression bymodulating the transcription for specific disease prevention.

Cas9 does not have to change for every DNA sequence to be targeted—onehas to reprogram it with a different RNA transcript, which is easy todesign and implement.

Furthermore, the CRISPR-Cas9 can be replaced by the CRISPR-Cpf1. Cas9requires two RNA molecules to cut DNA and Cpf1 needs just one RNAmolecule. Both Cas9 and Cpf1 cut DNA at different places. Cas9 cuts bothstrands in a DNA molecule at a same position, leaving behind blunt endsand blunt ends can be repaired by sticking the two ends back together,in a repair process which can leave errors. However, Cpf1 cuts DNA in adifferent way, leaving one strand in a DNA molecule longer than theother—thus creating a sticky end.

Cas9 is an RNA-directed DNA-binding protein, guided by a single guideRNA. By inactivating its nuclease activity, coupling the protein toother effector domains and choosing an appropriate guide sequence, itcan direct activities in a specific part of the genome. The nanoshell120 (encapsulating/caging CRISPR-Cas9 system) can be decorated with thetargeting ligand 200 to recognize/match/bind with specific biologicalreceptors on stem cells (from pluripotent stem cells) to deliverCRISPR-Cas9 system into stem cells.

CRY2 and CIB1 are two plant proteins. In response to light, CRY2undergoes a conformational change that allows it to interact with CIB1.In an optogenetic CRISPR-Cas9 system: CRY2 is fused to thetransactivation domain (either p65 or VP64) and C1B1 is fused todCas9—the deactivated Cas9 nuclease from CRISPR. The optogeneticCRISPR-Cas9 system can enable precise spatial and temporal control ofcell behavior by light (e.g., blue light) and direct new DNA sequencesfor the dynamic regulation of endogenous genes. The nanoshell 120(encapsulating/caging the optogenetic CRISPR-Cas9 system) can bedecorated with targeting ligand 200 to recognize/match/bind withspecific biological receptors on stem cells (from pluripotent stemcells) to deliver the optogenetic CRISPR-Cas9 system into stem cells bylight.

The CRISPR-Cas9 or optogenetic CRISPR-Cas9 system can be inserted intostem cells via the nanoshell 120 to remove a key gene in a diseaseprocess and replace it with a beneficial gene that releases a biologicdrug—thus-creating the engineered stem cells.

For example, the CRISPR-Cas9 or optogenetic CRISPR-Cas9 system can beinserted into stem cells via the nanoshell 120 to remove a key gene inthe inflammatory process and replace it with a gene that releases abiologic drug (e.g., the tumor necrosis factor-alpha (TNF-alpha)inhibitor) to reduce inflammation via the engineered stem cells.Similarly, engineered stem cells can sense glucose and turn on insulinin response.

Example Applications of Gene Text Editing

HIV needs to latch onto a human body's white blood cell's CCR5 receptorsto invade cells. However, a genetic mutation in a human body's whiteblood-cell's CCR5 receptor can prevent transmission of the HIV virus.Thus, gene editing can be utilized to disable the specific genesresponsible for the production of CCR5 receptors.

Transcription Factor Control by Engineered CRISPR-Cas9 System with RNA

Transcription factors proteins can bind with specific DNA sequences inthe gene's promoter region for either recruiting or blocking the enzymesneeded to copy that gene into mRNA.

An engineered CRISPR-Cas9 system with RNA can act as a transcriptionfactor, wherein Cas9 complexed with a short 20-nucleotides segment ofRNA (matching the target DNA segment) can be programmed to target a DNAsequence, wherein Cas9 is disabled with a first protein to cut DNA afterbinding with DNA. Furthermore, the engineered CRISPR-Cas9 is embeddedwith a second protein (e.g., programmable oligomers), wherein the secondprotein can activate or repress gene expression by modulating thetranscription.

Molecular Coupling to a Virus/Programmed Suicide of a Virus InfectedCell to Inhibit Virus Multiplication/Propagation

The nanoshell 120 can be encapsulated/caged in the nanocarrier 160. Thenanocarrier 160 can be decorated with the first targeting ligand 200.The first targeting ligand 200 can recognize/match/bind with specificbiological receptors 240A on a cell to allow the nanoshell 120 to thecell infected with a virus.

The nanoshell 120 can be decorated with the second targeting ligand 220(e.g., an aptamer/protein kinase R (PKR) protein) which canrecognize/match/bind with a single stranded RNA/double strandedRNA/double stranded DNA of a virus). The nanoshell 120 can be uncappedin the cell infected with the virus, when the second targeting ligand220 recognizes/matches/binds with a single stranded RNA/double strandedRNA/double stranded DNA of the virus in the cell.

The bioactive compounds 100 and/or bioactive molecules 100A can bedelivered from the nanoshell 120 to induce the cell infected with thevirus for a programmed cell suicide (e.g., via apoptotic proteaseactivating factor 1) to inhibit the multiplication/propagation of thevirus.

However, for a specific application of molecular coupling to avirus/programmed suicide of a virus infected cell to inhibit virusmultiplication/propagation, only the nanoshell 120 (without thenanocarrier 160) can be utilized.

Molecular Coupling to a Cancer Cell/Programmed Suicide of a Cancer Cellto Inhibit Cancer Multiplication/Propagation

The nanoshell 120 can be encapsulated/caged in the nanocarrier 160. Thenanocarrier 160 can be decorated with the first targeting ligand 200.The first targeting ligand 200 can recognize/match/bind with specificbiological receptors 240A on a cancer cell to allow the nanoshell 120 tothe cancer cell.

The nanoshell 120 can be decorated with the second targeting ligand 220(e.g., a specific aptamer is designed to be complementary to an RNAsequence unique to a cancer cell). The nanoshell 120 can be uncapped inthe cancer cell, when the second targeting ligand 220recognizes/matches/binds with an RNA sequence unique to a cancer cell.

The bioactive compounds 100 and/or bioactive molecules 100A can bedelivered from the nanoshell 120 to induce a cancer cell 260 for aprogrammed cell suicide (e.g., via p53 pathway) to stop cancermultiplication/propagation.

For example, the bioactive compound 100,2-(4-morpholinoanilino)-6-cyclohexylaminopurine, a small bioactivemolecule can induce selectively cell death of a cancer cell.

For example, the bioactive compound 100, a Bax activator compound canbind directly and selectively to Bax for Bax activation. When activated,Bax damages the cell's mitochondria, releasing signals to self-destructthe cell and digest its pieces.

For example, the bioactive compound 100, Lomaiviticin A (or itschemical/structural analogue of Lomaiviticin A—e.g., Lomaiviticinaglycon), which can induce death of a cancer cell, by cleaving a cancercell's double strands of its DNA structure. The three-dimensionalstructure and structure of Lomaiviticin A are given below.

For example, the bioactive compound 100, ironoxide nanoparticle or thebioactive molecule 100A aspirin (a COX inhibitor molecule) can activateimmune cells (e.g., a tumor associated macrophage) to destroy a cancercell.

For example, the bioactive compound 100 or the bioactive molecule 100Acan be utilized to reprogram a corrupted/hijacked tumor associatedmacrophage by blocking its microRNA (e.g., Let-7 microRNA) to a humanbody's immune system.

For example, the bioactive compound 100 or the bioactive molecule 100Acan be utilized to inhibit Focal Adhesion Kinase (“FAK”) protein, whichis often overproduced in a cancer cell to evade attacks by a humanbody's immune system.

Cancer cells often utilize immune checkpoint molecules (e.g., PD-L1) todeceive/evade an attack by a human body's immune system (e.g., T cells,one group of white blood cells). For example, the bioactive compound 100(e.g., ipilimumab) or the bioactive molecule 100A (e.g., natural humanantibody) can be utilized as a checkpoint inhibitor, which can blockcheckpoint molecules on a cancer cell or proteins (e.g., programmeddeath-1 (PD-1)) on T cells in order to remove the blinders thatgenerally prevent T cells from recognizing a cancer cell.

However, for a specific application of molecular coupling to a cancercell/programmed suicide of a cancer cell to inhibit cancermultiplication/propagation (e.g., utilizing extra copies of p53protein), only the nanoshell 120 (without the nanocarrier 160) can beutilized.

Raising an amount of zinc via a bioactive compound (e.g., zincmetallochaperones) in a cancer cell can cause p53 protein to fold rightback up and function normally. The recovered p53 protein can promptapoptosis. A bioactive compound to raise zinc amount in a mutated p53protein can be delivered by the nanoshell 120.

The addition of iron nanoparticles and/or anti-SIRPα antibodies (e.g.,rituximab) to a tumor associated macrophage (TAM) can switch a tumorassociated macrophage to attack a cancer cell. Iron nanoparticles can bedelivered to a tumor associated macrophage by the nanoshell 120.

Molecular Coupling to Inhibit Insulin Degrading Enzyme

Normally about 50% of the insulin produced by the pancreas isimmediately destroyed by the liver; but there may be a mechanism toregulate how much insulin enters into a human body's bloodstream.Insulin degrading enzyme is a protease, an enzyme that chops proteins orpeptides into smaller pieces. If insulin degrading enzyme is inhibited,insulin can remain in a human body's blood stream longer. Insulindegrading enzyme is involved in a surprisingly wide range of importantprocesses, including memory and cognition. Thus, insulin degradingenzyme inhibitors may have multiple therapeutic applications. Insulindegrading enzyme is a thiol-sensitive zinc-metallopeptidase.

A short-lived insulin degrading enzyme inhibitor, taken before a mealcan be beneficial to manage Type-2 Diabetes disease.

By way of an example and not by way of any limitation, a bioactivecompound C₂₁H₂₂FN₃O₅S₂ with the structural formula (as described below)can inhibit insulin degrading enzyme.

The nanoshell 120 can be encapsulated/caged in the nanocarrier 160. Thenanocarrier 160 can be decorated with the first targeting ligand 200.The first targeting ligand 200 can recognize/match/bind with specificbiological receptors 240A on a cell to allow the nanoshell 120 to thecell.

The nanoshell 120 can be decorated with the second targeting ligand 220(e.g., a specific aptamer is designed to bind with a specific target oninsulin degrading enzyme). The nanoshell 120 can be uncapped in thecell, when the second targeting ligand 220 recognizes/matches/binds withthe specific target of insulin degrading enzyme to deliver the bioactivecompound such as, C₂₁H₂₂FN₃O₅S₂ to inhibit insulin degrading enzyme.

Molecular Coupling to Inhibit Insulin Degrading Enzyme Integrated withIn-Vivo Gene Regulation by a Synthetic/Engineered Riboswitch

Just as natural riboswitches can regulate gene expression in response tosmall-molecule ligands during transcription or translation, syntheticriboswitches can be engineered to repress or activate gene expression ina ligand-dependent fashion. A riboswitch can be turned on or off by asmall molecule. Such riboswitch biosensors would provide spatial as wellas temporal information regarding the levels of specific ligands indisease and the input information can be used to regulate cellularbehavior for achieving therapeutic goals.

The nanoshell 120 can be encapsulated/caged in the nanocarrier 160. Thenanocarrier 160 can be decorated with the first targeting ligand 200.The first targeting ligand 200 can recognize/match/bind with specificbiological receptors 240A on a cell to allow the nanoshell 120 to thecell. The nanoshell 120 can be decorated with the second targetingligand 220 (e.g., a specific aptamer is designed to bind with a specifictarget on insulin degrading enzyme). The nanoshell 120 can be uncappedin the cell, when the second targeting ligand 220recognizes/matches/binds with the specific target of insulin degradingenzyme to deliver the bioactive compound such as, C₂₁H₂₂FN₃O₅S₂ toinhibit insulin degrading enzyme and a riboswitch engineered torecognize glucose as its ligand and in response, the riboswitchengineered to recognize glucose as its ligand and in response, regulatesthe expression of insulin degrading enzyme gene in-vivo.

Example Applications of a Nanoshell (can be Decorated with a HumanBody's Red Blood Cell Membrane & Polyethylene Glycol Membrane) without aNanocarrier Collective Intelligence from Quorum Sensing of a Large Arrayof Smart Nanoshells

DNA structure can assemble into a two-dimensional and/or athree-dimensional nanomechanical device. This two-dimensional and/or athree-dimensional nanomechanical device can be further integrated with(a) a targeting ligand (e.g., a specific aptamer/RNA) and abiocompatible nanosensor (e.g., an exosome) to act as a smart nanoshell120. The smart nanoshell 120 can be activated by using a targetingligand to deliver bioactive compounds 100 and/or bioactive molecules100A.

Collective intelligence (e.g., swarm intelligence acquired from quorumsensing of the biocompatible nanosensors) of a large array of smartnanoshells 120 s can be derived/utilized to predict the efficacy of thebioactive compounds 100 and/or bioactive molecules 100A for a treatmentand/or to diagnose a disease and/or an array of diseases.

In many cases of, constrained applications, the nanoshell 120 (withoutthe nanocarrier 160) coated with an immune shielding functional surface180 can be utilized.

The nanoshell 120 (coated with a light sensitive layer or chemicallycoupled with wavelength converting nanoparticles) can be activated by asuitable wavelength from an external light source (e.g., anultraviolet/visible/infrared light source) to deliver the bioactivecompounds 100 and/or bioactive molecules 100A from the nanoshell 120 tothe cell 260.

Alternatively, the nanoshell 120 (alternatively, configured with amagnetic nanoparticle) can be activated by a suitable external magneticfield to deliver the bioactive compounds 100 and/or bioactive molecules100A from the nanoshell 120 to the cell 260.

A specific small interfering RNA can be designed to suppress/inhibitunwanted protein manufacturing in the cell 260. The specific smallinterfering RNA can be encapsulated/caged in the nanoshell 120. Thenanoshell 120 decorated with a targeting ligand can deliver the specificsmall interfering RNA to suppress/inhibit specific unwanted proteinmanufacturing to the cell 260.

Molecular Coupling to a Virus/Programmed Death of a Virus Infected Cellto Inhibit Virus Multiplication/Propagation

To sense an invading virus, a cell can use a pattern recognitionreceptor. The pattern recognition receptor can recognize/match/bind to amolecular signature, specific to the virus. This binding causes thepattern recognition receptors to change its structural shape. Thus,initiating a chain-reaction of a signal (regarding the virus) to thesurrounding cells.

For example, one of these pattern recognition receptors is RIG-1, whichcan practically target all RNA viruses. In an absence of a virus, amolecular virus sensor of RIG-1 receptor is exposed, while the domainresponsible for cell signaling is hidden out of reach of the signalingmachinery.

But when the RIG-1 receptor detects a virus it changes its shape—wakingup the cell signaling domains and triggering interferon production inthe cell.

The changing shape of the RIG-1 receptor can be detected upon binding ofthe molecular virus sensor of the RIG-1 receptor with a molecular probetargeting ligand (e.g., a molecular beacon) wherein the molecular probeis configured with a suitable fluorophore.

The molecular probe (configured with a suitable fluorophore) targetingligand can be decorated on the nanoshell 120.

Furthermore, the bioactive compounds 100 and/or bioactive molecules 100Afor programmed cell suicide can be encapsulated/caged in/with anultra-sensitive photolabile protecting group (PPG). The photolabileprotecting group can be encapsulated/caged in the nanoshell 120.

Thus, in-vivo fluorescence can trigger a release of the bioactivecompounds 100 and/or bioactive molecules 100A from the photolabileprotecting group for programmed cell suicide (e.g., via apoptoticprotease activating factor 1) of the virus infected cell to inhibitvirus multiplication/propagation.

However, instead of the RIG-1 receptor, the nanoshell 120 can bedecorated with a specific targeting ligand. The specific targetingligand can recognize/match/bind with a single stranded RNA/doublestranded RNA/double stranded DNA of a virus.

Molecular Coupling to a Virus/Programmed Death of a Virus Infected Cellto Inhibit Virus Multiplication/Propagation Utilizing DNA/RNA OrigamiStructure Smart Nanoshell

The (DNA/RNA origami structure based) nanoshell 120 can befabricated/constructed, inputting a list of DNA/RNA strands that can bemixed together, by utilizing DNA/RNA modeling software.

DNA/RNA modeling software can predict how DNA/RNA base pairs canbind/match together to create a particular DNA/RNA origami structure.

The (DNA/RNA origami structure based) nanoshell 120 can be decoratedwith a targeting ligand (e.g., a specific aptamer) torecognize/match/bind a target molecule in the signaling domain of theRIG-1 receptor, when the RIG-1 receptor changes its shape in thepresence of a virus.

When the targeting ligand and target molecule recognize/match/bind inthe signaling domain of the RIG-1 receptor, when the RIG-1 receptorchanges its shape in the presence of a virus, the DNA strand can beconfigured to unzip, unlocking the (DNA/RNA origami structure based)nanoshell 120 and releasing the bioactive compounds 100 and/or bioactivemolecules 100A for programmed cell suicide (e.g., via apoptotic proteaseactivating factor 1) of a virus infected cell to inhibit virusmultiplication/propagation.

However, instead of the RIG-1 receptor, the (DNA/RNA origami structurebased) nanoshell 120 can be decorated with a specific targeting ligand.The specific targeting ligand can recognize/match/bind with a singlestranded RNA/double stranded RNA/double stranded DNA of a virus.

To enhance specificity, two targeting ligands can be utilized, insteadof one targeting ligand.

Thus, it would require two different matching signals in order to unzipthe (DNA/RNA origami structure based) nanoshell 120.

Synthesis of Protein On-Demand

An amino acid, DNA/modified DNA (wherein the DNA/modified DNAencapsulated/caged in/with a photolabile protecting group) and aribosome can be encapsulated/caged in the nanoshell 120.

For example, a nanosized hole in DNA can be drilled by an atomic beam toinsert/delete a suitable atom or a molecule in order tofabricate/construct the modified DNA.

An incident light can activate the photolabile protecting group tosynthesize a desired protein on-demand in-vitro and in-vivo. Thenanoshell 120 can then deliver the desired protein directly to the cell260. The desired protein can be utilized as a treatment against adisease.

Synthesis of Protein On-Demand by Synthetic Nucleotides

The natural genetic alphabet of DNA, the As, Cs, Gs, and Ts that writesthe stories/book of life can be integrated (chemically bonded) with newcompatible synthetic letters (e.g., α and β) to create a hybrid DNA (towrite expanded stories/books of life). Furthermore, the hybrid DNA canbe integrated (chemically bonded) with an importin protein(s). Importinis a type of protein that can transport its cargo hybrid DNA into thenucleus by binding to a specific recognition sequence, called thenuclear localization signal (NLS). Importin protein can bind with itscargo hybrid DNA in the cytoplasm, after which they are able to interactwith the nuclear pore complex and pass through its channel. Once insidethe nucleus, interaction with Ran-GTP causes a conformational change inthe importin protein that causes it to dissociate from its cargo hybridDNA. The nanoshell 120 decorated with a targeting ligand, wherein thetargeting ligand can recognize/match/bind with specific receptors of acell—thus allowing the cell membrane to be opened for the passage of thenanoshell 120 to deliver hybrid DNA integrated (chemically bonded) withan importin protein in cytoplasm and then ultimately into the nucleus.

Utilizing an artificial messenger RNA, hybrid DNA can manufacture usefulprotein(s)/protein(s)—on Demand, unknown to exist in nature, leading toa large number of amino acids and proteins. For example, adding just two(2) synthetic alphabets of DNA, one can manufacture one hundredseventy-two (172) amino acids with three (3) base pairs such as αβA orTGα.

Furthermore, a hybrid DNA code can be used to build hybrid biologicalcircuits (in cells) which may/may not interfere with the naturalbiological circuits.

Alzheimer's Disease

Shape and/or electrical polarity of the nanoshell 120 can be importantparameters to suppress/inhibit Alzheimer's disease.

A tubular shaped nanoshell 120 can enhance/promote amyloid beta protein,increasing rate of decline in cognitive abilities in a human brain.

A negative electrical charged and tetrahedral shaped nanoshell 120 candistort and suppress/inhibit amyloid beta protein, significantlydecreasing rate of decline in cognitive abilities in a human brain.

A specific small interfering RNA can be designed to suppress/inhibitunwanted protein manufacturing in the cell 260. A specific smallinterfering RNA can be encapsulated/caged in the nanoshell 120. Thenanoshell 120 decorated with a targeting ligand, wherein the targetingligand can recognize/match/bind with adenosine receptors—thus allowing ahuman body blood-brain barrier to be opened for the passage of thenanoshell 120 to deliver a specific small interfering RNA tosuppress/inhibit unwanted protein manufacturing in a human brain.

Increased CD33 protein activity in microglia can impair amyloid betaprotein. More CD33 proteins are on the cell surface of microglia; thenmore amyloid beta proteins-toxic amyloid beta plaques and damagingdebris are in a human brain. Thus, reducing or silencing CD33 proteinmay be beneficial against Alzheimer's disease. The nanoshell 120decorated with a targeting ligand, wherein the targeting ligand canrecognize/match/bind with adenosine receptors—thus allowing a humanbody's blood-brain barrier to be opened for the passage of the nanoshell120 to deliver a specific small interfering RNA to suppress/inhibit CD33protein manufacturing in a human brain. However, it should be noted thata certain version of the CD33 gene may decrease CD33 protein activity inmicroglia.

Alzheimer's disease can be caused by a loss of synapses (betweenneurons) due to disintegration of tau protein, wherein tau protein caninteract with amyloid beta protein.

Aging and/or poor autophagy can upregulate amyloid precursor proteincleaving enzyme: Bacel (β-secretase-a molecular scissor).

Bacel (β-secretase) can cut amyloid precursor protein to produce amyloidbeta protein and another small fragment called AICD. Both amyloid betaprotein and AICD can be linked to Alzheimer's disease. If Bacel isacetylated via activation of ATase1 enzyme and ATase2 enzyme, then Bacelcan travel through the cell in a series of steps to produce amyloidprecursor protein. If Bacel is not acetylated, then Bacel takes adifferent pathway toward degradation.

RanBP9 protein can push amyloid precursor protein at the cell (neuroncell) edge, wherein both Bacel and presenilin complex (γ-secretase-amolecular scissor) can cut amyloid precursor protein to generate amyloidbeta protein.

A potential prevention and/or treatment of Alzheimer's disease can beachieved by suppressing/inhibiting RanBP9 protein manufacturing. RanBP9protein is encoded by RanBP9 gene.

Curcumin (e.g., a nanoformulated curcumin) can suppress/inhibit RanBP9protein manufacturing in a human brain.

Cucurbitacin (e.g., Cucurbitacin E) can suppress/inhibit RanBP9 proteinmanufacturing in a human brain. Nanoformulated cucurbitacin can enhancethe efficacy and/or bioavailability at a lower concentration.

Metformin (N,N-dimethylimidodicarbonimidic diamide) can suppress/inhibitRanBP9 protein manufacturing in a human brain.

An anticancer compound imatinib mesylate can suppress/inhibit RanBP9protein manufacturing in a human brain. But imatinib mesylate cannotpass through a human body's blood-brain barrier

Imatinib mesylate is4-[(4-Methyl1-piperazinyl)methyl]-N-[4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-phenyl]benzamidemethanesulfonate and its structural formula is shown below:

The molecular formula of Imatinib mesylate is C₂₉H₃₁N7O—CH₄SO₃ and itsmolecular weight is 589.7.

Imatinib mesylate can be encapsulated/caged in the nanoshell 120. Thenanoshell 120 decorated with a targeting ligand, wherein the targetingligand can recognize/match/bind with adenosine receptors—thus allowing ahuman body's blood-brain barrier to be opened for the passage of thenanoshell 120 to deliver imatinib mesylate to suppress/inhibit RanBP9protein manufacturing in a human brain.

Nanoformulated imatinib mesylate can enhance the efficacy and/orbioavailability at a lower concentration.

Sodium phenylbutyrate can suppress/inhibit RanBP9 protein manufacturingin a human brain.

An anticancer compound dasatinib can suppress/inhibit RanBP9 proteinmanufacturing in a human brain.

The dasatinib isN-(2-chloro-6-methylphenyl)-2-[[6-[4-(2-hydroxyethyl)-1-piperazinyl]-2-methyl-4-pyrimidinyl]amino]-5-thiazolecarboxamide,monohydrate and its structural formula is shown below:

The molecular formula of dasatinib is C₂₂H₂₆ClN₇O₂S.H₂O and itsmolecular weight is 506.02 (monohydrate).

Nanoformulated dasatinib can enhance the efficacy and/or bioavailabilityat a lower concentration.

Dasatinib can be encapsulated/caged in the nanoshell 120. The nanoshell120 decorated with a targeting ligand, wherein the targeting ligand canrecognize/match/bind with adenosine receptors—thus allowing a humanbody's blood-brain barrier to be opened for the passage of the nanoshell120 to deliver dasatinib to suppress/inhibit RanBP9 proteinmanufacturing in a human brain.

Affibody molecule (an engineered protein) can be encapsulated/caged inthe nanoshell 120. The nanoshell 120 decorated with a targeting ligand,wherein the targeting ligand can recognize/match/bind with adenosinereceptors—thus allowing a human body's blood-brain barrier to be openedfor the passage of the nanoshell 120 to deliver affibody molecule tosuppress/inhibit formation of amyloid beta protein in a human brain.

PARK7 gene (known as DJ-1) can protect cells (neurons) against oxidativedamage. Sodium phenylbutyrate and/or a short protein fragment ofnon-mutated PARK7 can turn on PARK7 gene (known as DJ-1) to protectagainst oxidative damage.

Sodium phenylbutyrate and/or a short protein fragment of non-mutatedPARK7 can be encapsulated/caged in the nanoshell 120. The nanoshell 120decorated with a targeting ligand, wherein the targeting ligand canrecognize/match/bind with adenosine receptors—thus allowing a humanbody's blood-brain barrier to be opened for the passage of the nanoshell120 to deliver sodium phenylbutyrate and/or a short protein fragment ofnon-mutated PARK7 to protect against oxidative damage.

Glial cell line-derived neurotrophic factor (GDNF) protein can nourishdopamine neurons by activating survival and growth-promoting pathwaysinside the neurons of a human brain. But glial cell line-derivedneurotrophic factor protein is limited in its ability to cross a humanbody's blood-brain barrier. The nanoshell 120 decorated with a targetingligand, wherein the targeting ligand can recognize/match/bind withadenosine receptors—thus allowing a human body's blood-brain barrier tobe opened for the passage of the nanoshell 120 to deliver glial cellline-derived neurotrophic factor protein to protect against damage ofdopamine neurons.

Oleocanthal (its structural formula is shown below), a phenoliccomponent of extra-virgin olive oil can reduce risk of Alzheimer'sdisease by clearing toxic amyloid beta protein from a human brain via upregulation of (a) P-glycoprotein (P-gp) and (b) low-density lipoproteinreceptor-related protein (LRP1). P-glycoprotein and low-densitylipoprotein receptor-related protein are major amyloid beta transportproteins at a human body's blood-brain barrier. However, thebioavailability of oleocanthal is unknown.

The nanoshell 120 decorated with a targeting ligand, wherein thetargeting ligand can recognize/match/bind with adenosine receptors—thusallowing a human body's blood-brain barrier to be opened for the passageof the nanoshell 120 to deliver oleocanthal to protect againstAlzheimer's disease.

The receptor for advanced glycation end products (RAGE) is a transporterof amyloid beta protein across a human body's blood-brain barrier into ahuman brain from the systemic circulation, while low-density lipoproteinreceptor-related protein mediates transport of amyloid beta protein outof the brain. Accumulation of amyloid beta protein leading toAlzheimer's disease can be due to a relative distribution/ratio ofreceptor for advanced glycation end products protein and low-densitylipoprotein receptor-related protein. However, the nanoshell 120decorated with a targeting ligand, wherein the targeting ligand canrecognize/match/bind with adenosine receptors—thus allowing a humanbody's blood-brain barrier to be opened for the passage of the nanoshell120 to deliver bioactive compounds 100 and/or bioactive molecules 100Aand/or small interfering RNA to suppress/inhibit receptor for advancedglycation end products manufacturing to protect against Alzheimer'sdisease.

Stress/corticosteroid can cause the 5-lipoxygenase to overexpress andincrease its levels which in turn increases the levels of the amyloidbeta protein and tau protein. The nanoshell 120 decorated with atargeting ligand, wherein the targeting ligand can recognize/match/bindwith adenosine receptors—thus allowing a human body's blood-brainbarrier to be opened for the passage of the nanoshell 120 to deliverbioactive compounds 100 and/or bioactive molecules 100A and/or smallinterfering RNA to suppress/inhibit 5-lipoxygenase protein manufacturingto protect against Alzheimer's disease.

Amyloid beta protein can injure synapses directly by inducing therelease of excessive amounts of neurotransmitter glutamate from braincells named astrocytes, located near neurons. Normal levels of glutamatecan promote memory and learning, but excessive levels are very harmful.Excessive glutamate activates extrasynaptic receptors, designated aseNMDA receptors (N-methyl-D-aspartate). These eNMDA receptors can behyperactivated—thus leading to synaptic loss. Memantine, a positivelycharged molecule can be easily repelled by positively diseased neurons;minimizing memantine's effectiveness, as it chemically binds with eNMDAreceptors. Nitroglycerin can also bind eNMDA receptors. Nitroglycerin,isosorbide dinitrate and isosorbide mononitrate can convert into nitricoxide by mitochondrial aldehyde dehydrogenase and nitric oxide is apotent natural vasodilator. A combination of memantine and nitroglycerin(or isosorbide dinitrate or isosorbide mononitrate) can reduce excessiveglutamate—thus protecting against Alzheimer's disease. Such acombination can include a chemical derivative or a structural analog ofnitroglycerin (or isosorbide dinitrate or isosorbide mononitrate).Furthermore, the nanoshell 120 decorated with a targeting ligand,wherein the targeting ligand can recognize/match/bind with adenosinereceptors—thus allowing a human body's blood-brain barrier to be openedfor the passage of the nanoshell 120 to deliver bioactive compounds:memantine and nitroglycerin (or isosorbide dinitrate or isosorbidemononitrate) to protect against Alzheimer's disease.

GLYX-13 (a small molecule) mimics an antibody and targets NMDA(N-methyl-Daspartate) receptors on neurons' surface. These NMDAreceptors help control synaptic plasticity and neuro-chemical basis oflearning, memory and depression. The nanoshell 120 decorated with atargeting ligand, wherein the targeting ligand can recognize/match/bindwith adenosine receptors—thus allowing a human body's blood-brainbarrier to be opened for the passage of the nanoshell 120 to deliverbioactive compounds: GLYX-13 to protect against Alzheimer's disease.

Amyloid beta protein can bind with LilrB2 on neuron-cell surfaces—thusupregulating cofilin activity to destroy synapses' structural integrity.Furthermore, the nanoshell 120 decorated with a targeting ligand,wherein the targeting ligand can recognize/match/bind with adenosinereceptors—thus allowing a human body's blood-brain barrier to be openedfor the passage of the nanoshell 120 to deliver bioactive compounds 100and/or bioactive molecules 100A to protect against binding of amyloidbeta protein binding with LilrB2.

Angiotensin-converting enzyme (ACE) is a naturally occurring enzyme thatcan have either detrimental or beneficial effects, depending on how andwhere it is active. Angiotensin-converting enzyme contributes toproduction of angiotensin II, a hormone that often causes blood vesselsto narrow and blood pressure to rise; inhibiting the enzyme relaxesvessels and reduces pressure. But in the brain, high levels ofangiotensin-converting enzyme quickly and efficiently lead an immunesystem response against beta-amyloid protein. Furthermore, the nanoshell120 decorated with a targeting ligand, wherein the targeting ligand canrecognize/match/bind with adenosine receptors—thus allowing a humanbody's blood-brain barrier to be opened for the passage of the nanoshell120 to deliver bioactive compounds 100 and/or bioactive molecules 100Afor overexpressing angiotensin-converting enzyme to protect againstAlzheimer's disease.

Benzyl quinolone carboxylic acid (BQCA) and/or Benzoquinazoline-12(BQZ-12) can be encapsulated/caged in a nanoshell 120 to protect againstAlzheimer's disease.

Long-acting insulin derivative[2-sulfo-9fluroenylmethoxycarbonyl]-3insulin can be encapsulated/cagedin a nanoshell 120. The nanoshell 120 can be delivered for inhale viaintranasal administration to protect against Alzheimer's disease.

Furthermore, intranasal administration can include stem cells to protectagainst Alzheimer's disease or other neurological diseases. Furthermore,intranasal administration can include engineered (engineered to expresscertain genes) stem cells to protect against Alzheimer's disease orother neurological diseases.

Cancer Disease

Bee venom contains a potent toxin called melittin that can poke holes ina cancer cell. However, large amounts of free melittin can also cause alot of damage to healthy cells.

An assassin protein perforin can be a cancer's weapon of massdestruction. Perforin is encoded by the PRF1 gene. Perforin is expressedin T cells and natural killer (NK) cells. Interestingly, perforinresembles a cellular weapon employed by a bacterium (e.g., anthrax).Perforin has the ability to embed itself to form a pore in acell-membrane. The pore by itself may be damaging to a cell and itenables the entry of a toxic enzyme granzyme B, which induces anapoptosis (a programmed suicide process) of a cancer cell.

The nanoshell 120 with melittin (its structural formula is shown below)can attack a cancer cell.

The nanoshell 120 with both melittin and/or perforin can attack a cancercell.

Cancer cells have a significantly increased rate of mitosis—thus cancercells are significantly more vulnerable to toxic poisoning than arenormal cells.

Colchicine is a toxic natural product and secondary metabolite,originally extracted from plants of the genus Colchicum. Colchicine onlybecomes active and detonates when in contact with an enzyme found insolid tumors sparing healthy tissue. The nanoshell 120 with colchicineat a low dose can attack a cancer cell.

The nanoshell 120 can collapse-enabling it to deliver encapsulated/cagedsmall molecules/synthetic notch molecules to T cells for activation.

Alternatively, the nanoshell 120 can encapsulate/cage an encoding genefor chimeric antigen receptors/CARs and specifically deliver theencapsulated/caged encoding gene for converting T cells to CAR T cells.CAR T cells' action onto cancer cells can be also controlled by smallmolecules/synthetic notch molecules. Additionally, the nanoshell 120 canbe coupled with nanoparticles to convert near-infrared light intovisible blue light.

Alternatively, the nanoshell 120 encapsulating/caging a smallinterfering RNA to suppress liver receptor homolog 1 (LRH-1) to inhibitenormous glutamine metabolism of cancer cells.

Alternatively, the nanoshell 120 encapsulating/caging a smallinterfering RNA and/or a suitably charged (either positive polarity ornegative polarity) small molecule and/or a notch signaling moleculeand/or a small molecule to turn off a pyramid-shaped K-Ras molecularswitch to inhibit growth of cancer cells. Additionally, the nanoshell120 can be coupled with nanoparticles to convert near-infrared lightinto visible blue light.

Alternatively, the nanoshell 120 (e.g., fabricated/constructed by DNAorigami) can encapsulate/cage an advanced encoding gene for advanced(consisting of a signaling domain(s)) chimeric antigen receptors(advanced CARs) and specifically deliver the encapsulated/caged advancedencoding gene for converting T cells to advanced CAR T cells. Theadvanced CAR T cells' action onto cancer cells can be also controlled bysmall molecules/synthetic notch molecules.

Additionally, checkpoint inhibitors, such as PD-1 inhibitors and/oranti-CTLA4 (anti-cytotoxic T-lymphocyte antigen 4) specific bioactivecompounds 100 can also be integrated with T cells/CAR T cells/advancedCAR T cells.

The nanoshell 120 can be integrated with a targeting ligand (e.g., aspecific antibody/aptamer) to bind specifically with a specific cancercell. Such nanoshell 120 encapsulating/encaging lauric acid (a phasechange material) as a carrier for a free radical generating compound(s)(e.g., an azo compound AIPH) can deliver the free radical generatingcompound(s), when a near-infrared laser heats up the nanoshell 120,causing lauric acid to melt and triggering the release of AIPH.

The nanoshell 120 can be integrated with a fluorescent probe molecule toilluminate cancer cells for locating purposes.

Alternatively, the fluorescent probe molecule can be chemicallyintegrated with the targeting ligand.

The nanoshell 120 can be integrated with a photodynamic sensitizermolecule for detecting a specific cancer cell.

Alternatively, the nanoshell 120 can be integrated with a magneticnanoparticle to guide the nanoshell 120 to a specific cancer cell by amagnetic field.

The nanoshell 120 can deliver the bioactive compounds 100 and/orbioactive molecules 100A to cancer cells (for therapy/treatment) underan external stimulus (e.g., pH).

Diabetes Disease

Long-acting insulin derivative[2-sulfo-9fluroenylmethoxycarbonyl]-3insulin and leptin (or a chemicalderivative/structural analog of leptin) can be encapsulated/caged in apH responsive nanoshell 120. The pH responsive nanoshell 120 can bedelivered for oral intake/inhale.

Long-acting insulin derivative[2-sulfo-9fluroenylmethoxycarbonyl]-3insulin and oleoylethanolamide(OEA) (or a chemical derivative/structural analog of oleoylethanolamide)can be encapsulated/caged in a pH responsive nanoshell 120. The pHresponsive nanoshell 120 can be delivered for oral intake/inhale.

Oleoylethanolamide (or a chemical derivative/structural analog ofoleoylethanolamide) can be encapsulated/caged in a pH responsivenanoshell 120. The pH responsive nanoshell 120 can be delivered for oralintake/inhale.

A specific small interfering RNA can be designed to suppress/inhibitcryptochrome protein manufacturing. The specific small interfering RNAcan be encapsulated/caged in the nanoshell 120. The nanoshell 120 candeliver the specific small interfering RNA to suppress/inhibitcryptochrome protein manufacturing.

Hearing Loss Disease

Free radicals can induce manufacturing of Bak, a protein. Bak proteincan trigger suicide of cells (these cells do not regenerate like othercells in a human body) in the auditory portion of the inner ear.

The level of Bak protein can also increase with aging.

A specific small interfering RNA can be designed to suppress/inhibit Bakprotein manufacturing. The specific small interfering RNA can beencapsulated/caged in the nanoshell 120. The nanoshell 120 can deliverthe specific small interfering RNA (locally through the round windowmembrane (RWM) of the inner ear) to suppress/inhibit Bak proteinmanufacturing in a human ear.

Cochlear hair cell apoptosis (cell death)—a key factor in several formsof acute hearing loss, can be induced by p53 protein. However, aninhibition of p53 protein can be achieved by specific small interferingRNA. The specific small interfering RNA can be encapsulated/caged in thenanoshell 120. The nanoshell 120 can deliver the specific smallinterfering RNA (locally through the round window membrane of the innerear) to suppress/inhibit p53 protein manufacturing in a human ear.

The administration of the bioactive compounds 100 and/or bioactivemolecules 100A to treat hearing loss disease is through the permeationof the round window membrane. The ultra-fine structures of the roundwindow membrane are not well known, but there are vesicles in the roundwindow membrane, wherein clathrin and caveolin pathways may be involvedin the transportation of the nanoshell 120 through round windowmembrane.

Mammalian hearing loss due to damage to auditory hair cells is normallyirreversible. The Notch signaling pathway represents a criticalcomponent in the molecular circuits that control cell fate and plays aregulatory role in oxidative stress. But a partial recovery of auditoryhair cells can be possible by inhibiting the Notch signaling pathway,utilizing (a) curcumin, (b) niclosamide(5-chloro-N-2-chloro-4-nitrophenyl)-2-hydroxybenzamide) and (c) aγ-secretase inhibitor.

Furthermore, the nanoshell 120 can be decorated with targeting ligands,which can bind to specific receptors on spiral ganglion cells (Trk-Breceptors) and on the vasculature (the matrix metalloproteins, MMP2).

Brain-derived neurotrophic factor (BDNF) protein can also interact withTrk-B receptors.

Furthermore, cell entry of the nanoshell 120 can be facilitated by aviral-TAT peptide (e.g., TAT-Influenza-HA), binding of the nanoshell 120with Trk-B receptors can be facilitated by brain-derived neurotrophicfactor ligand and the nuclear pore complex entry of the nanoshell 120can be facilitated by a nuclear targeting peptide.

Furthermore, brain-derived neurotrophic factor protein, Atoh1/Math1 gene(for growth of hair cells), a small interfering RNA designed tosuppress/inhibit Bak protein manufacturing in a human ear) can beencapsulated/caged in the nanoshell 120.

Reactive oxygen species are involved in cisplatin-induced hearing loss.It depresses significantly the levels of antioxidant enzymes, superoxidedismutase, glutathione peroxidase, glutathione reductase, glutathionetransferase and catalase—all antioxidants that protect cells from freeradicals. Similarly, free radicals elevate the levels of products oflipid peroxidation, a process in which free radicals degrade the cellmembrane. It also depletes the level of glutathione, another importantantioxidant. When hair cells become damaged, glutamate (an excitatoryneurotransmitter responsible for converting vibrational sounds intoelectrical signal) is produced in excessive amounts. Excessive amountsof glutamate can be toxic to neurons.

Coenzyme Q₁₀ (ubiquinol) can delay progression of hearing loss inpatients with a genetic defect (7445A→G mitochondrial mutation).Although, supplementation with a single antioxidant may produce somebeneficial effects in improving hearing disorders. However, a singleantioxidant in a high oxidative environment can even act as apro-oxidant.

The nanoshell 120 can deliver a synergistic combination ofacetyl-L-carnitine, alpha-lipoic acid, glutathione, magnesium,n-acetylcysteine (NAC), 4-hydroxyphenyl N-tert-butyl nitrone/4-OHPBNnitrone and coenzyme Q₁₀ (ubiquinol) or ubiquinol (coenzyme Q₁₀) toreduce hearing loss.

Some photochemicals protect cells by disrupting established pathways byblocking activation of pro-inflammatory genes. Different photochemicalshave different ways of interfering with toll-like receptors andnucleotide binding oligomerization domain containing proteins.

Furthermore, the nanoshell 120 can deliver a synergistic combination ofcurcumin and resveratrol and selenium (selenomethionine) to reducehearing loss. Curcumin can undermine certain toll-like receptors when aspecific part of curcumin's chemical structure-known as a betaunsaturated carboxyl group reacts with so-called sulfhydryl groups intoll-like receptors. Resveratrol can also interfere with moleculescalled TBK1 and RIP1. TBK1 and RIP1 convey signals to and from toll-likereceptors. But when resveratrol interacts with TBK1 and RIP1, however,the effect is somewhat like a traffic light, which controls the flow ofvehicles on a busy street.

Furthermore, the nanoshell 120 can deliver neurotrophin to reducehearing loss.

Exposure to a high intensity noise can cause a decrease in totalantioxidant capacity and an increase in nitric oxide. Increased nitricoxide can cause formation of peroxynitrite, which is very damaging tohair cells. The nanoshell 120 can deliver a combination ofanticonvulsant zonisamide and glucocorticoid (e.g., methylprednisoloneor betamethasone phosphate (BP)) to cochleae (cochleae is a Hopfoscillator acting as a nonlinear power amplifier, boosting weak signalsmuch more than strong ones) over a sustained period of time to reducehearing loss due to a high intensity noise.

Hepatitis B, Hepatitis C, HIV & Other Deadly Virus Based Diseases

Bee venom contains a potent toxin called melittin that can poke holes inthe double-layered membranes indiscriminately of a virus (e.g.,hepatitis B, hepatitis C and HIV). However, large amounts of freemelittin can also cause a lot of damage to healthy cells.

In contrast, most anti-HIV drugs inhibit the virus's ability toreplicate. But this anti-replication strategy does nothing to stopinitial infection and some mutated strains of the virus have found waysaround these drugs and reproduce anyway.

An assassin protein perforin can be a virus's weapon of massdestruction. Perforin is encoded by the PRF1 gene. Perforin is expressedin T cells and natural killer cells. Interestingly, perforin resembles acellular weapon employed by a bacterium (e.g., anthrax). Perforin has anability to embed itself to form a pore in a cell-membrane. The pore byitself may be damaging to a cell and it enables the entry of a toxicenzyme granzyme B, which induces an apoptosis (a programmed suicideprocess) of a diseased cell.

The nanoshell 120 with melittin can attack an essential part of thevirus' (e.g., hepatitis B, hepatitis C and HIV) structure to destroy thevirus.

The nanoshell 120 with melittin and perforin in combination can attackan essential part of the virus' (e.g., hepatitis B, hepatitis C and HIV)structure to destroy the virus.

The nanoshell 120 with a targeted small interfering RNA can attack anessential part of the virus' (e.g., hepatitis B, hepatitis C and HIV)structure to destroy the virus.

The nanoshell 120 a targeted small interfering RNA in combination withmelittin can attack an essential part of the virus' (e.g., hepatitis B,hepatitis C and HIV) structure to destroy the virus.

The nanoshell 120 a targeted small interfering RNA in combination withperforin can attack an essential part of the virus' (e.g., hepatitis B,hepatitis C and HIV) structure to destroy the virus.

The nanoshell 120 a targeted small interfering RNA in combination withmelittin and perforin can attack an essential part of the virus' (e.g.,hepatitis B, hepatitis C and HIV) structure to destroy the virus.

Furthermore, the virus destroying strategy as cited in previousparagraphs can be generally utilized to destroy other deadly virusstrains (e.g., Ebola). In the case of Ebola, a specific smallinterfering RNA is needed to silence the gene responsible forreplication-polymerase L.

The nanoshell 120 can be decorated with a targeting ligand (e.g., aspecific aptamer) to recognize/match/bind a target molecule in thesignaling domain of a receptor (e.g., TIM-1) of Ebola virus.

When the targeting ligand and target molecule recognize/match/bind inthe signaling domain of the receptor of Ebola virus, the nanoshell 120can release the specific small interfering RNA to inhibit replication ofpolymerase L.

However, instead of the receptor, the nanoshell 120 can be decoratedwith a specific targeting ligand to recognize/match/bind with a negativestranded RNA based Ebola virus (which means the genome consists of oneor more molecules of single stranded “antisense” RNA).

To enhance specificity, two targeting ligands can be utilized instead ofone targeting ligand.

Thus, it would require two different matching signals in order to unzipthe nanoshell 120.

Immune

An antigen/antibody generator can evoke the production of one or moreantibodies. Each antibody binds to a specific antigen by way of aninteraction similar to fit between a lock and a key. The antigen canoriginate from within a human body or external environment. The immunesystem can destroy or neutralize any antigen that is recognized as aforeign/potentially harmful invader.

The nanoshell 120 with specific antigen or an array of antigens canprevent immune-mediated diseases (e.g., Type-1 Diabetes disease).Insulin is destroyed in Type-1 Diabetes disease, because the autoimmunedisease kills the beta cells producing that antigen. The nanoshell 120with insulin can delay the onset or prevent Type-1 Diabetes disease.

The nanoshell 120 with myelin antigens can be engulfed by macrophages, atype of immune cell. Macrophages can then display the antigens on theircell surface. The nanoshell 120 with myelin antigens can inhibit theactivity of myelin responsive T cells.

Inflammation

Reactive oxygen species can cause an inflammation in cardiovascular,hearing loss, infection and neurological diseases. An accumulation ofreactive oxygen species can result in manifestation hydrogen peroxide(H₂O₂) or hypochlorous acid. Furthermore, an onset of reactive oxygenspecies related inflammation in cardiovascular, hearing loss, infectionand neurological diseases can be approximately correlated with massiveoxidative stress (thus, accumulation of hydrogen peroxide in the hairfollicle), decreased antioxidant capacities including catalase,thioredoxin reductase and the repair mechanisms methionine sulfoxidereductases.

A synergistic combination of about 200 mg of catalase (or a chemicalderivate or a structural analog of catalase or a pseudocatalaseactivated via sunlight), about 200 mg of glutathione peroxidase, about1000 mg of L-methionine, about 100 mg of methionine sulfoxide reductase(MSR), about 200 mcg of selenium amino acid complex (sodium selenite,L-selenomethionin and selenium-methyl L-selenocysteine), about 200 mgsuperoxide dismutase and about 200 mg of Emblica officinalis extract canreduce damages due to free radicals and hydrogen peroxide in the hairfollicle.

Hydrogen peroxide or hypochlorous acid sensitive nanoshell 120 candegrade in the presence of a minute amount of hydrogen peroxide orhypochlorous acid in order to deliver the bioactive compounds 100 and/orbioactive molecules 100A to reduce the inflammation in cardiovascular,hearing loss, infection and neurological diseases.

Inflammation in a human is an earlier indicator of Alzheimer's disease.A pathway involving TYROBP (an inflammatory gene) can interact withTREM2, a gene involved in Alzheimer's disease. TREM2-TYROBP pathway canplay an initial role in driving Alzheimer's disease. TargetingTREM2-TYROBP pathway early on may delay/decrease risk of developingAlzheimer's disease.

TL1A protein takes part in driving the inflammation. The nanoshell 120with the specific small interfering RNA can be utilized to block TL1Aprotein production.

Premature Aging (Progeria) Disease

A cellular instability leading to premature aging (Progeria) disease canbe caused by toxic Lamin A protein. Toxic Lamin A protein ismanufactured due to a mutation in the LMNA gene. A specific smallinterfering RNA can be designed to suppress/inhibit toxic Lamin Aprotein manufacturing. The nanoshell 120 can deliver the specific smallinterfering RNA to suppress/inhibit toxic Lamin A protein manufacturing.

Furthermore, Lamin A protein interacts with SUN 1 protein. The nanoshell120 can deliver the specific small interfering RNA to suppress/inhibitSUN 1 protein manufacturing.

Protein Misfolding Disease

The complexity and dynamics of unfolded proteins can play a crucial rolein aggregation, misfolding and subsequent diseases (e.g., Alzheimer'sand Diabetes diseases).

Fragments of misfolded proteins can seed and then coerce/recruit normalprotein to misfold and propagate various neurological diseases (e.g.,Alzheimer's and Prion diseases) relentlessly. In the case of Alzheimer'sdisease, the proteins' individual amino acids can be assembled intostrands, which stack into sheets that run the length of the entirestructure. Those sheets can then group with increasing rigidity intoprotofilaments, filaments and finally mature and tough fibrils. Besidesthe intricate structure, many of the packing interactions are derivedfrom the amyloid self-assembly process.

The reconfiguration dynamics of unfolded proteins may be governed byphysics of thermodynamics. The reconfiguration dynamics can be measuredby the rate of intramolecular diffusion (the diffusion rate of one partof a protein sequence with respect to another part).

The nanoshell 120 decorated with a first targeting ligand 200, whereinthe first targeting ligand 200 can recognize/match/bind with adenosinereceptors—thus allowing a human body's blood-brain barrier to be openedfor the passage of the nanoshell 120 to deliver the bioactive compounds100 and/or bioactive molecules 100A for prevention ofaggregation/misfolding (e.g., bioactive compound nanocurcumin canprevent aggregation/misfolding on alpha-synuclein) by shifting theintramolecular diffusion rate out of the danger range.

Furthermore, the nanoshell 120 can be decorated with a second targetingligand, wherein the second targeting ligand can recognize/match/bindwith a suitable part of an aggregation-prone protein sequences. Thenanoshell 120 can then deliver the bioactive compounds 100 and/orbioactive molecules 100A for prevention of proteinaggregation/misfolding.

It is critical to prevent protein aggregation/misfolding at a very earlystage of a neurological disease, so that the rogue protein may not beable to seed and then coerce/recruit normal protein to misfold andpropagate a neurological disease.

Protozoan Infection

Natural artemisinin (from sweet wormwood plant/Artemesia annua L) can bean effective treatment against protozoan infection-P. falciparummalaria. When artemisinin comes in contact with high concentrations ofiron (ferrous compounds generally found in protozoan infection-P.falciparum malaria), a chemical reaction is produced to create freeradicals that attack cell membranes, breaking them apart and killingprotozoan infection-P. falciparum malaria. Genes (e.g., encodingdehydrogenase enzymes) from Artemesia annua L can be inserted intosuitable genes (with more rare words (codons) near the start of thegenes) of bacterium/yeast to produce artemisinic acid, a precursor ofsynthetic artemisini. Artemisinic acid can be photochemically convertedto artemisini. Similarly, bacterium/yeast can produce the anticancercompound taxol and the anti-HIV compound prostratin. It should be notedthat synthetic OZ439 bioactive compound can be an alternative toartemisini.

Furthermore, the nanoshell 120 can be decorated with a targeting ligand,wherein the targeting ligand can recognize/match/bind with a suitablepart of protozoan infection-P. falciparum malaria. The nanoshell 120 canthen deliver the bioactive compounds (e.g., artemisini or OZ439) totreat against protozoan infection-P. falciparum malaria.

Superbug Infection

An antibiotic is a bioactive compound that kills/slows down the growthof bacteria by a mechanism like: (a) inhibiting the cell wall synthesis,(b) blocking DNA/RNA expression, (c) stopping the folic acid synthesis,(d) disrupting cell membrane permeability and arresting the centraldogma of bacteria (DNA, RNA and protein synthesis) and (e) inhibitingthe protein synthesis.

But superbugs embody a group of bacteria which contains severalresistance genes which when expressed leads to development of antibioticresistance by a mechanism like: (a) coding for specific enzymes whichdevastate antibiotics, (b) modifying the efflux pump which causestrans-shipment of antibiotic out of the bacterial cell, (c) modifyingthe configuration of target site so that antibiotics cannot bind withthe bacterial cell and (d) production of alternative target (enzyme) tobind the antibiotics. In short, bacterial resistance is due to eithertransformation or transduction or conjugation.

For example, New Delhi metallo-beta-lactamase-1 (NDM-1) is a genecarried by bacteria, which is responsible for producing an enzyme,carbapenemase within the bacteria making them resistant to (almost all)the present antibiotics.

The nanoshell 120 can be coated with positively chargeddimethyldecylammonium chitosan methacrylate. The interaction ofpositively charged dimethyldecylammonium chitosan methacrylate with thenegatively charged bacterial cell wall can result in the disintegrationof bacterial cell wall.

The nanoshell 120 can be decorated with the enzyme Lysostaphin, anatural enzyme and/or a compound configured for releasing nitric oxideand/or a compound configured for releasing reactive oxygen speciesand/or a compound configured for releasing reactive nitrogen species.Lysostaphin attacks the bacterial cell wall causing its slicing anddisintegration. The reactive oxygen species and/or reactive nitrogenspecies can modify the essential protein in bacteria causing bacterialcell death.

With more and more antibacterials and antibiotics, strains of bacteriacan evolve or mutate into superbugs, which are resistant toantibacterial drug(s). These drug resistant superbugs include CREbacteria, clostridum difficile and methicillin-resistant Staphylococcusaureus (MRSA). Methicillin-resistant Staphylococcus aureus cells cangrow to about 1 million cells in a day.

The nanoshell 120 can be decorated with a biomarker binder (e.g., anaptamer), which is very specific to a superbug. The nanoshell 120(containing multivalent adhesion molecule 7 (MAM7) encapsulated/cagedinside the nanoshell 120) with negatively charged electrical surface canbe drawn to the positively charged cell surface of a superbug (e.g.,methicillin-resistant Staphylococcus aureus), wherein multivalentadhesion molecule 7 can disable/disrupt adhesion of a superbug.

The nanoshell 120 can be decorated with a biomarker binder (e.g., anaptamer), which is very specific to a superbug. The nanoshell 120(containing melittin from bee venom and/or an assassin protein perforinencapsulated/caged inside the nanoshell 120) with negatively chargedelectrical surface can be drawn to the positively charged cell surfaceof a superbug (e.g., methicillin-resistant Staphylococcus aureus).

Melittin and/or perforin can pierce through the cell membrane of thesuperbug. Thus, only the contents of the cell of the superbug arespilled out and the superbug is destroyed without harming any healthycells.

An immune system called the CRISPR-Cas system is present in manybacteria. The CRISPR-Cas system protects a bacterium from an invader(e.g., a virus) by creating small strands of RNA calledCRISPR-RNAs—matching the specific DNA sequences of the invader. WhenCRISPR RNAs find a match, the bacterium unleashes Cas proteins to cutthe DNA of the invader. Conversely, a designer clustered regularlyinterspaced short palindromic repeats (CRISPR) RNAs can target DNAsequences in the bacterium, as a bacterium's CRISPR-Cas system attacksits own DNA, causing bacterium to suicide. The nanoshell 120 (containinga designer CRISPER RNAs-targeting DNA sequences in the bacterium,encapsulated/caged inside the nanoshell 120) can cause a superbug tosuicide, without harming any healthy cells. Additionally, the nanoshell120 can be decorated with a targeting ligand (e.g., a specific aptamer)to specifically bind with the particular superbug.

Diseases of Mind-Depression

Ketamine (with its structural formula is shown below) binds to andblocks a receptor in a human brain called NMDA receptor. Ketaminetriggers both anesthetic and antidepressant effects.

Like an electroshock therapy, ketamine eases depression by blocking aneurotransmitter called glutamate from binding to the NMDA receptor onneurons.

Too much glutamate on the NMDA receptor, can lead to the opening of acalcium ion channel—thus releasing too much calcium downstream—thusaffecting a brain chemical brain-derived neurotrophic factor protein.

Ketamine causes neurons to make more brain-derived neurotrophic factorprotein, which increases connections between neurons in the brain. Theseconnections can help the brain regulate emotions better and reset thebackground activity of a human brain.

Ketamine (used in the easing depression) can be delivered at anextremely low dose and over a longer period.

The nanoshell 120 decorated with a targeting ligand, wherein thetargeting ligand can recognize/match/bind with adenosine receptors—thusallowing a human body's blood-brain barrier to be opened for the passageof the nanoshell 120 to deliver ketamine at an extremely low strength.

However, instead of NMDA receptor, the bioactive compounds 100 and/orbioactive molecules 100A can activate eEF2 protein to treat depression.

Psilocybin, a prodrug of psilocin (4-hydroxy-dimethyltryptamine) canalso ease depression. Psilocybin can decrease cerebral blood flow (CBF)after its use.

The nanoshell 120 decorated with a targeting ligand, wherein thetargeting ligand can recognize/match/bind with adenosine receptors—thusallowing a human body's blood-brain barrier to be opened for the passageof the nanoshell 120 to deliver psilocybin at an extremely low dose.

Alternatively, the nanoshell 120 decorated with a targeting ligand,wherein the targeting ligand can recognize/match/bind with adenosinereceptors—thus allowing a human body's blood-brain barrier to be openedfor the passage of the nanoshell 120 to deliver ibogain (derived fromTabermanthe iboga) at an extremely low dose.

Furthermore, there are about 100 trillion microbes in the gut. Leakygut/displaced bacteria can activate inflammation and autoimmuneresponse(s), which are responsible for onset of depression and fatigue.

Glutamine, N-accetylcysteine and zinc or combination of glutamine,N-accetylcysteine and zinc (L-Opti) can be encapsulated/caged in ananoshell 120. The nanoshell 120 can deliver appropriate amounts ofglutamine, N-accetylcysteine and zinc or combination(s) of glutamine,N-accetylcysteine and zinc to reduce inflammation and autoimmuneresponse(s) for the leaky gut—thereby delaying the onset of depressionand fatigue.

Reprogramming of an Epigenetic Marker

Changes in the epigenome do not change a gene's sequence, but rather itsactivity level. The environment (e.g., diet and exercise) can alter theepigenome, changing the activity level of genes to raise or lower therisk for developing a disease, but also appear to influence theepigenome of future generations. Epigenetic modifications can influencedisease susceptibility, potentially lasting through several generations.Due to a phenomenon of genomic imprinting, maternal and paternal genomesare differentially marked and must be properly reprogrammed every timethey pass through the germline. Many genes may be coated with methylgroups. When a cell divides, the cellular memory is passed on from onegeneration to the next generation.

Reprogramming refers to an erasure and/or a remodeling of epigeneticmarks (e.g., DNA methylation) accumulated from previous generations.

Trichostatin A (C₁₇H₂₂N₂O₃) (with its structural formula is shown below)into a human brain can remove the methyl groups and behavioral deficits.

Trichostatin A has low-toxicity. To reduce toxicity of trichostatin Afurther, the nanoshell 120 decorated with a targeting ligand, whereinthe targeting ligand can recognize/match/bind with adenosinereceptors—thus allowing a human body's blood-brain barrier to be openedfor the passage of the nanoshell 120 to deliver trichostatin A at anextremely low dose.

Delivery of Bioactive Compounds &/or Bioactive Molecules from aNanoshell: A Nanoshell Configured with a Bacterium/Microbe/GeneticallyEngineered Microbe

The nanoshell 120 can be configured with a harmless bacterium (e.g.,lactobacillus)/microbe/genetically engineered microbe to deliver thebioactive compounds 100 and/or bioactive molecules 100A.

Delivery of Bioactive Compounds &/or Bioactive Molecules from aNanoshell Configured with a Nanopump

Prestin is a motor protein enabling direct voltage-to-force converter.

An engineered bacteria battery-M13 bacteriophage can translatemechanical energy into electrical energy. To improve the piezoelectricproperty of M13 bacteriophage, the outer protein layer of M13bacteriophage can be engineered by adding appropriate molecules.

Furthermore, to amplify piezoelectric effect, multi-layers of engineeredM13 bacteriophage can be utilized. Multi-layers of engineered M13bacteriophage can then be sandwiched between two biocompatibleelectrodes to act as a battery, when stressed mechanically.

A thin-film battery/thin-film printed battery/biofuel battery/engineeredbacteria battery coupled with prestin motor protein can befabricated/constructed, as a nanopump (or as an array of nanopumps withnetworks of prestin motor proteins).

Alternatively, a thin-film battery/thin-film printed battery/biofuelbattery/engineered bacteria battery coupled with phi29 DNA polymeraseenzyme can be fabricated/constructed, as a nanopump (or as an array ofnanopumps with an array of phi29 DNA polymerase enzymes).

A nanopump can generate a sustained mechanical wave in the nanoshell 120to release/eject the bioactive compounds 100 and/or bioactive molecules100A from the nanoshell 120.

Delivery of Bioactive Compounds &/or Bioactive Molecules from aNanotube/Nanotube Configured with a Nanopump

A nanotube (e.g., a boron nitride/carbon nanotube or atubular/tetrahedral structure, fabricated/constructed, utilizing DNA/RNAorigami process) can cross a cell membrane and enter the nuclei of thecell, while the cell may not recognize the nanotube as an unfriendlyintruder. The nanotube can be biodegradable and less toxic.

The uptake of the bioactive compounds 100 and/or bioactive molecules100A from a solution into the nanotube can be achieved by van der Waalsattraction between the nanotube and the bioactive compounds 100 and/orbioactive molecules 100A.

The nanotube's exterior surface can be coated with (a) an optionalprotective (to protect from a human body's blood/biological fluid)functional surface and (b) an immune shielding (to protect from a humanbody's inherent immune surveillance) functional surface.

Furthermore, the nanotube's exterior surface can be decorated with atargeting ligand to recognize/match/bind with specific biologicalreceptors on the cell to allow aft entry of the nanotube to the cell.

Therefore, the bioactive compounds 100 and/or bioactive molecules 100Acan be delivered to the cell with unprecedented accuracy and efficiency.

Prestin is a motor protein enabling direct voltage-to-force converter. Athin-film battery/thin-film printed battery/biofuel battery/engineeredbacteria battery coupled with prestin motor protein can befabricated/constructed, as a nanopump (or as an array of nanopumps withnetworks of prestin motor proteins).

Alternatively, a thin-film battery/thin-film printed battery/biofuelbattery/engineered bacteria battery coupled with phi29 DNA polymeraseenzyme can be fabricated/constructed, as a nanopump (or as an array ofnanopumps with an array of phi29 DNA polymerase enzymes).

A nanopump can generate a sustained mechanical wave in the nanotube torelease/eject the bioactive compounds 100 and/or bioactive molecules100A from the nanotube.

Targeted Delivery to Mitochondria

The mitochondria are the power plants of cells. Mitochondria generatemost of the cell's supply of adenosine triphosphate (ATP). Adenosinetriphosphate is used as a source of chemical energy.

While mitochondria are present in all cells, in some cells, because oftheir size and purpose—it is necessary to transport mitochondria atproper positions within the cell to maintain proper function of thecell.

For example, neurons have a complex cellular structure of a main cellbody and enormous arms of axons and dendrites that fan out from the cellcore and transmit signals to adjoining cells via synapses at theirtermini.

Thus, the supply chain to mitochondria is very long. Mitochondria arealso constantly cycling throughout the neuron. Neurons can transportmitochondria (some mitochondria are stationary/fixed, while othermitochondria are mobile) down the enormous arms of axons and dendritesat proper positions to provide other parts of the cell with energy, helpwith the transmission of signals and maintenance of the cellular health.

Additionally, at any given time about half of the mobile mitochondria inthe neurons are returning to the cell to be recycled/replenished.

One interesting property of mitochondria is that they have their ownDNA. Mitochondrial DNA is different from chromosomal/nuclear DNA. First,it exists as a simple plasmid (a DNA loop) than the chromosomal/nuclearDNA. Second, most repair mechanisms to correct chromosomal/nuclear DNAare missing from mitochondrial DNA. Thus, relativelyunprotected/unrepairable mitochondrial DNA can suffer about 10 timesmore damage than chromosomal/nuclear DNA.

Mitochondrial electron transport is not perfect. Even under idealmitochondrial conditions, some electrons can leak from the electrontransport chain. These leaking electrons can interact with oxygen toproduce superoxide radicals.

Furthermore, with mitochondrial dysfunction, leakage of electrons canincrease significantly.

The close proximity of mitochondrial DNA to the flux of superoxideradicals (or hydroxyl radicals) and the lack of mitochondrialprotection/repair mechanism can lead to mitochondrial dysfunction.

Many diseases can be related to mitochondrial dysfunction—thus anability to transport the bioactive compounds 100 and/or bioactivemolecules 100A to mitochondria specifically can be beneficial.

Furthermore, the disruptive changes to mitochondria can occur, when bothamyloid beta protein and tau protein (rather truncated version of tauprotein, not regular version of tau protein) are present together andthe disruptive changes are: (a) about 30% remaining electrical potential(but 100% electrical potential is needed to produce energy efficiently),(b) abnormal mitochondria clumping, (c) fragmentation of mitochondria,(d) incorrect control of calcium level and (e) release of (toxic) freeradicals.

Triphenylphosphonium can pass through and accumulate several hundredfolds in mitochondrial matrix.

The bioactive compounds 100 and/or bioactive molecules 100A can bechemically coupled with triphenylphosphonium/chemical derivative oftriphenyl phosphonium/structural analog of triphenylphosphonium toenhance an uptake of the bioactive compounds 100 and/or bioactivemolecules 100A in mitochondria.

Passive Micropatch

FIG. 7A illustrates an expanded view of a negative electrical chargedsurface 180A on the bioactive compound 100.

FIG. 7B illustrates an expanded view of a negative electrical chargedsurface 180A on the bioactive molecule 100A.

FIG. 7C illustrates an expanded view of a nanocrystal 120A.

FIG. 7D illustrates an expanded view of a positive electrical chargedsurface 180B on the nanocrystal 120A.

The charge conjugation can increase the encapsulation efficiency and/ordelivery efficiency of the bioactive compounds 100 and/or bioactivemolecules 100A.

FIG. 7E illustrates an expanded view of a fluorophore (e.g., a quantumdot fluorophore) 120B. Furthermore, the fluorophore 120B can be a dye(e.g., ATTO/Alexa Fluor 488 dye or photostable diarylmethylene-bridgednaphthophosphole P-oxide dye) based fluorophore or a fluorescentprotein.

With a quantum dot fluorophore, the size of the bandgap can becontrolled by varying the diameter of the quantum dot. Larger diameter(e.g., 10 nanometers in diameter) quantum dot fluorophore will have asmaller bandgap—thus the larger diameter quantum dot fluorophore willfluoresce in the red part of the optical spectrum. Conversely, smallerdiameter (e.g., 5 nanometers in diameter) quantum dot fluorophore willhave a larger bandgap—thus the smaller diameter quantum dot fluorophorewill fluoresce in the blue part of the optical spectrum.

FIG. 7F illustrates 120C, wherein the negative electrical chargedbioactive compounds 100 and/or bioactive molecules 100A are surroundedby a cluster of the positive electrical charged nanocrystals 120A.

FIG. 7G illustrates 120D, wherein 120C is chemically bonded with theimmune shielding functional surface 180.

FIG. 7H illustrates 120E, wherein 120D can be chemically bonded with aspecific targeting ligand 220A.

FIG. 7I illustrates 120F, wherein 120E is optionally chemically bondedwith the fluorophore 120B.

The above nanoassembly 7I can be utilized for targeted delivery of thebioactive compounds 100 and/or bioactive molecules 100A.

FIG. 7J illustrates a microelectromechanical systems reservoir 300.

The microelectro-mechanical-system reservoir 300 can befabricated/constructed, utilizing liquid-crystalpolymers/polyimide/silicon/silk/SU-8 resin/other suitable material.

FIG. 7K illustrates 120Fs. 120Fs are inserted/caged in themicroelectro-mechanical-system reservoir 300.

FIG. 7L illustrates the top surface 300B of themicroelectro-mechanical-system reservoir 300. 300B can be attached ontoa non-porous adhesive top thin-film 320A.

The porous bottom surface of the microelectro-mechanical-systemreservoir 300 is 300A. 300A can be attached onto a biological transportmedium (e.g., skin) for delivery of the bioactive compounds 100 and/orbioactive molecules 100A.

Thus, a long-term passive micropatch (about 15 millimeters² in area)(with the porous bottom surface of the microelectro-mechanical-systemreservoir) can be fabricated/constructed for the delivery of thebioactive compounds 100 and/or bioactive molecules 100A.

The porous bottom surface of the microelectro-mechanical-systemreservoir 300 is 300A. The porous bottom surface of (themicroelectro-mechanical-system reservoir 300) 300A can be attached ontoa nanoporous membrane (e.g., a nanoporous membrane of titanium dioxidenanotubes or a carbon nanomembrane), then onto a biological transportmedium for delivery of the bioactive compounds 100 and/or bioactivemolecules 100A.

Thus, a long-term passive micropatch (about 15 millimeters² in area)(with the porous bottom surface of the microelectro-mechanical-systemreservoir and nanoporous membrane) can be fabricated/constructed for thedelivery of the bioactive compounds 100 and/or bioactive molecules 100A.

FIG. 7M illustrates 120F bonded directly between a non-porous top(adhesive) thin-film 320A and a porous bottom (adhesive) thin-film 320B.The porous bottom (adhesive) thin-film 320B can be attached onto abiological transport medium.

The non-porous top (adhesive) thin-film 320A can utilize chitin (abiopolymer based on the N-acetyl-glucosamine monomer) and/or chitin'svariant deacetylated counterpart chitosan and/or fibroin (a proteinderived from silk) as a base material/protective coating material forthe non-porous top (adhesive) thin-film 320A.

Thus, a short-term passive micropatch (about 15 millimeters² in area)with the porous bottom (adhesive) thin-film 320B can befabricated/constructed for the delivery of the bioactive compounds 100and/or bioactive molecules 100A.

Furthermore, a specific vaccine can be preserved by drying in sugar.Then the sugar-dried vaccine can be fabricated/constructed, as an arrayof dissolvable microneedles. Such an array of dissolvable microneedlescan be embedded with the porous bottom (adhesive) thin-film 320B, forthe instant delivery of the vaccine.

Passive Micropatch of Porous Nanofiber Mesh

Electrospinning uses an electric field to catapult a charged fluid jetthrough air to create very fine nanometer-scale fibers (e.g.,biocompatible material/material mixtures of alginate and/or chitinand/or fibroin) and it can be manipulated to control the material'ssolubility, strength and geometry.

A nanofiber mesh can be stretched to physically block a human body'sblood/biological fluid and/or deliver the bioactive compounds 100 and/orbioactive molecules 100 through the nanofiber mesh.

The nanofiber mesh can incorporate many fibers with variable propertiesto deliver the bioactive compounds 100 and/or bioactive molecules 100through the nanofiber mesh at different delivery rates to increase thepotency. The nanofiber mesh can be used on or in a human body.

Two-Dimensional Array of Nanosized Wells of a Porous Material, as anAlternative to A Microelectro-Mechanical-System Reservoir

Alternatively, a two-dimensional array of nanosized wells of a suitableporous material (e.g., porous hydrogel/porous silicon/silicate basedpolymer nanocomposite) containing the bioactive compounds 100 and/orbioactive molecules 100A (or indirectly, utilizing nanocrystals, whereinthe nanocrystals encapsulate/cage the bioactive compounds 100 and/orbioactive molecules 100A) can replace the abovemicroelectro-mechanical-system reservoir 300 in both thelong-term/short-term passive micropatch.

The two-dimensional array of nanosized wells of the suitable porousmaterial thin-film can be fabricated/constructed, utilizing lithography(e.g., phase mask/electron beam lithography) and inductively-coupledplasma (ICP) etching/focused ion beam etching.

The two-dimensional array of nanosized wells of the suitable porousmaterial thin-film can be functionalized with peptide nucleic acid (PNA)probes to target distinguishing different bacterial strains (e.g., S.aureus and E. coli).

Furthermore, the two-dimensional array of nanosized wells of thesuitable porous material thin-film can be functionalized with peptidenucleic acid probes to target simultaneous identification of resistantand non-resistant E. coli, causing urinary tract infections.

Smart Porous Thin-Film, as an Alternative to aMicroelectro-Mechanical-System Reservoir

A smart thin-film (e.g., a composite-gel) can regulate permeability inresponse to an external stimulus.

The smart thin-film can contain an ordered array of nanochannels.Furthermore, the ordered array of nanochannels can contain an orderedarray of magnetic polystyrene latex particles.

The magnetic polystyrene latex particle can change its size in responseto an external stimulus (e.g., temperature). Expansion/contraction ofthe magnetic polystyrene latex particles can affect the permeability ofthe smart porous thin-film from on state to off state.

Thus, a controlled transport and/or a tunable transport of the bioactivecompounds 100 and/or bioactive molecules 100A can be achieved, byutilizing the suitable smart porous material thin-film.

Thus, in addition to delivering the bioactive compounds 100 and/orbioactive molecules 100A, utilizing the long-term/short-term passivemicropatch, other bio/health sensors to monitor vital health parameters(e.g., blood sugar and heart rate) can be integrated with thelong-term/short-term passive micropatch.

An example of a bio/health sensor integrated with thelong-term/short-term passive micropatch is in-situ blood sugarmeasurement. Blood sugar measurement can involve an electrochemicalreaction activated by an enzyme. Glucose oxidase can be convert glucoseinto hydrogen peroxide and other chemicals—thus their concentrations canbe measured with a miniature potentiostat or nanosized potentiostat as abiosensor for calculating the glucose level in sweat. Furthermore, thebio/health sensor can be integrated with an analog signal to a digitalsignal converter (ADC) circuit.

Wibree, Bluetooth, Wi-Fi and near-field communication can be integratedwith the long-term/short-term passive micropatch. Furthermore,ultrathin/bare-die electronic components, processor(s), sensors, lightemitting diodes, photodetectors on the substrate of thelong-term/short-term passive micropatch can be flexibly interconnectedto detect/measure for example, blood flow dynamics, pressure wavevelocity (a measure of blood pressure variation) and level ofoxygenation in a human blood. Additionally, by injecting tiny heatpulses, the long-term/short-term passive micropatch can measure a humanskin's thermal conductivity (related to hydration level). Such substrateof the long-term/short-term passive micropatch is biocompatible andpreferably is flexible/stretchable.

The long-term/short-term passive micropatch can be integrated with abio/health sensor or a wearable device. Details of a wearable devicehave been described/disclosed in U.S. Non-Provisional patent applicationSer. No. 14/999,601 entitled “SYSTEM AND METHOD OF AMBIENT/PERVASIVEUSER/HEALTHCARE EXPERIENCE”, filed on Jun. 1, 2016 and the entirecontents of this US Non-Provisional Patent Application are incorporatedherein.

Thus, the bio/health sensor integrated with the long-term/short-termpassive micropatch can deliver the bioactive compounds 100 and/orbioactive molecules 100A, utilizing the long-term/short-term passivemicropatch.

Example Applications of a Passive Micropatch

7M can be utilized as a passive micropatch to deliver a compound, drug,molecule (e.g., a micro RNA and small interfering RNA) and protein.

7M can be utilized as a passive micropatch to deliver an antibioticbioactive compound.

Furthermore, an antibiotic bioactive compound can be integrated withmagnesium oxide nanoparticles, self-assembling peptides (e.g., RADA16-I)and silver nanoparticles.

7M can be utilized as a passive micropatch to deliver the preprogrammedrelease of an array of growth factors for wound healing. Furthermore,the growth factors for wound healing can be photo activated/modulated(by a small quantity of reactive molecular species), utilizing alaser/an array of lasers of suitable wavelength and intensity.Furthermore, after a wound, epidermal cells can replicate and move intothe area of a wound to close it up and start the healing process. Thiscauses ionic/free radical concentrations to shift, a change thatgenerates subtle but characteristic electrical fields. The fields can bedetected by sensor arrays-printed onto the passive micropatch itself,wherein the passive micropatch can be fabricated/constructed on aflexible/stretchable substrate (e.g., manufactured by MC10 company).

7M can be utilized as a passive micropatch to deliver sildenafil.

7M can be utilized as a passive micropatch to deliver testosterone.

7M can be utilized as a passive micropatch to deliver luric acid and/oran isolated active protein from the Propionibacterium acnes phages fortreatment against acne.

Propionibacterium acnes phages, (a family of harmless viruses that liveon a human skin) are naturally programmed to kill the Propionibacteriumacnes, a bacterium that triggers acne.

Furthermore, 7M can be utilized as a passive micropatch to deliver amixture of suitable oils and/or luric acid and/or an isolated activeprotein from the Propionibacterium acnes phages for treatment againstacne.

7M can be utilized as a passive micropatch to deliver rivastigmine fortreatment against Alzheimer's disease.

7M can be utilized as a passive micropatch to deliver rotigotine fortreatment against Parkinson's disease.

7M can be utilized as a passive micropatch (as a transplant passivemicropatch) to deliver insulin-producing stem cells (by manipulatingboth the Wnt and Notch signals. Wnt enhances self-renewal of adultpancreatic stem cells and inhibiting Notch signaling increasesproduction of insulin) or cells against Type 1 Diabetes disease. Thepassive micropatch may also contain protein and immune suppressingbioactive compound to allow the insulin-producing cells/stem cells tosuccessfully graft, survive and function within a human body.

β-cell replication is difficult to control in a human body. A decreasein the function of θβ-cells late in life is the main cause of Type 2Diabetes disease. Betatrophin, a liver hormone stimulates β-cellreplication with remarkable efficiency. 7M can be utilized as a passivemicropatch to deliver betatrophin.

7M can be utilized as a passive micropatch to deliver a nanoshell 120decorated with a targeting ligand, wherein the targeting ligand canrecognize/match/bind with adenosine receptors—thus allowing a humanbody's blood-brain barrier to be opened for the passage of the nanoshell120 to deliver oxytocin (“the love hormone). The oxytocin hormone mayhelp build a long-lasting love.

A constant and low dose of psilocybin can calm the psychologicalturbulence of people afflicted with a number of conditions, includingdepression and/or alcohol addiction. 7M can be utilized as a passivemicropatch to deliver a nanoshell 120 decorated with a targeting ligand,wherein the targeting ligand can recognize/match/bind with adenosinereceptors—thus allowing a human body's blood-brain barrier to be openedfor the passage of the nanoshell 120 to deliver psilocybin.

Bacteria outnumber human cells about ten to one. A human body has acomplex network of bacteria.

Bacteria possess genes that can encode beneficial compounds and/ormolecules for a human body.

Furthermore, bacteria communicate/socialize (within similar and/ordissimilar species) via chemical molecular quorum sensing (also known asdiffusion/efficiency sensing).

The quorum sensing is like census-taking. Quorum sensing allows bacteriato communicate using secreted chemical signaling molecules calledautoinducers.

The quorum sensing can collectively regulate gene expressions ofbacteria.

The quorum sensing can collectively regulate good/bad behaviors ofbacteria.

7M can be utilized as a passive micropatch to deliver a pro-quorumsensing compound.

7M can be utilized as a passive micropatch to deliver an anti-quorumsensing compound. Such anti-quorum compounds are called disaccharidederivatives and they mimic a class of natural molecules known asrhamnolipids, which are produced and secreted by the bacterium itself.Such compounds have the potential to inhibit horizontal gene transfer,the process by which bacteria share genetic information, such as theability to be drug-resistant.

7M can be utilized as a passive micropatch to deliver multivalentadhesion molecule 7 (MAM7) to disable/disrupt adhesion of bacteria.

7M can be utilized as a passive micropatch to deliver melittin and/orperforin to protect against Hepatitis B.

7M can be utilized as a passive micropatch to deliver melittin and/orperforin to protect against Hepatitis C.

7M can be utilized as a passive (vaginal) micropatch to deliver melittinand/or perforin to protect against HIV. However, the passive (vaginal)micropatch (to deliver melittin and/or perforin) can be coated withsuper hydrophilic nanoparticle to prevent breakage.

7M can be utilized to deliver granulocyte macrophage colony-simulatingfactor (GMC-SF), which can reprogram a human body's immune system toattack cancer cells.

7M can be integrated/impregnated with cell penetrating peptides. Cellpenetrating peptides (e.g., IMT-P8/various fomulations of IMT-P8) cantransport a bioactive compound/bioactive molecule/nanoparticle/nucleicacid/peptide/protein/small molecule/small interfering RNA through humanskin.

Active Micropatch Integrated with an Electrically Controlled Layer

The porous bottom thin-film 320B can be composed of electrically charged(an opposite electrical charge polarity with respect to the electricalcharge polarity of nanocrystals 120A) pigmented layers. Electricallycharged pigmented layers can hold (an opposite electrical chargepolarity) electrically charged nanocrystals 120A by an electrostaticfield.

By applying a voltage (about a few millivolts from a thin-film printedbattery), the electrically charged pigmented layers can disintegrate.

Thus, the bioactive compounds 100 and/or bioactive molecules 100A can bedelivered in a variable quantity from the electrically chargednanocrystals 120A.

Active Micropatch Integrated with an Electrically Controlled Layer & aSmart Porous Thin-Film

The porous bottom thin-film 320B can be composed of a smart thin-film. Asmart thin-film (e.g., a composite-gel) can regulate permeability inresponse to an external stimulus. The smart thin-film can contain anordered array of nanochannels. Furthermore, the ordered array ofnanochannels can contain an ordered array of magnetic polystyrene latexparticles. The magnetic polystyrene latex particle can change its sizein response to an external stimulus (e.g., temperature).Expansion/contraction of the magnetic polystyrene latex particles canaffect the permeability of the smart porous thin-film from an on stateto an off state.

Thus, a controlled transport and/or a tunable transport of the bioactivecompounds 100 and/or bioactive molecules 100A can be achieved, byutilizing the smart porous material thin-film.

Thus, in addition to delivering the bioactive compounds 100 and/orbioactive molecules 100A, utilizing the active micropatch, otherbio/health sensors to monitor vital health parameters (e.g., blood sugarand heart rate) can be integrated with the active micropatch.

An example of a bio/health sensor integrated with the active micropatchis in-situ blood sugar measurement. Blood sugar measurement can involvean electrochemical reaction activated by an enzyme. Glucose oxidase canconvert glucose into hydrogen peroxide and other chemicals—thus theirconcentrations can be measured with a miniature potentiostat ornanosized potentiostat as a biosensor for calculating the glucose levelin sweat. Furthermore, the bio/health sensor can be integrated with ananalog signal to a digital signal converter circuit.

Wibree, Bluetooth, Wi-Fi and near-field communication can be integratedwith the active micropatch. Furthermore, ultrathin/bare-die electroniccomponents, processor(s), sensors, light emitting diodes, photodetectorson the substrate of the active micropatch can be flexibly interconnectedto detect/measure for example, blood flow dynamics, pressure wavevelocity (a measure of blood pressure variation) and level ofoxygenation in a human blood. Additionally, by injecting tiny heatpulses, the active micropatch can measure human skin's thermalconductivity (related to hydration level). Such substrate of the activemicropatch is biocompatible and preferably flexible/stretchable.Furthermore, thin-film digital/source-gated transistor based circuits,as an artificial skin can be integrated with the active micropatch foron-demand delivery of the bioactive compounds 100 and/or bioactivemolecules 100A.

The active micropatch integrated with a bio/health sensor or a wearabledevice. Details of a wearable device have been described/disclosed inU.S. Non-Provisional patent application Ser. No. 14/999,601 entitled“SYSTEM AND METHOD OF AMBIENT/PERVASIVE USER/HEALTHCARE EXPERIENCE”,filed on Jun. 1, 2016 and the entire contents of this US Non-ProvisionalPatent Application are incorporated herein.

Thus, the bio/health sensor integrated with the active micropatch canenable active (actively controlled via closed loop measurement) deliveryof the bioactive compounds 100 and/or bioactive molecules 100A,utilizing the active micropatch.

An active micropatch can be placed (attached and/or implanted) on or in(meaning within) a human body

Example Applications of an Active Micropatch Integrated withElectrically Controlled Layer

NAD is a key molecule that coordinates activities between the cell'snuclear genome and the mitochondrial genome. With aging, levels of NADdecline. Without sufficient NAD, SIRT1 cannot keep tabs on HIF-1. Levelsof HIF-1 can escalate and begin wreaking havoc on the cross-genomecommunication. Over time, this loss of communication reduces the cell'sability to make energy and signs of ageing related diseases becomeapparent. By administering an endogenous compound (that cells cantransform into NAD) such as, plasma NAD metabolites-nicotinamidemononucleotide, one could restore cross-genome communication, if theendogenous compound was administered early enough, prior to excessivemutation accumulation. An active micropatch can be utilized to deliveran endogenous compound (that cells can transform into NAD) to delayonset of ageing related diseases.

An active micropatch can be utilized to deliver a compound, drug andmolecule (e.g., a micro RNA and small interfering RNA.

An active micropatch can be utilized to deliver an antibiotic bioactivecompound.

Furthermore, an antibiotic bioactive compound can be integrated withmagnesium oxide nanoparticles, self-assembling peptides (e.g., RADA16-I)and silver nanoparticles.

An active micropatch can be utilized to deliver the preprogrammedrelease of an array of growth factors for wound healing. Furthermore,the growth factors for wound healing can be photo activated/modulated(by a small quantity of reactive molecular species), utilizing alaser/an array of lasers of suitable wavelength and intensity.Furthermore, after a wound, epidermal cells can replicate and move intothe area of a wound to close it up and start the healing process. Thiscauses ionic/free radical concentrations to shift, a change thatgenerates subtle but characteristic electrical fields. The fields can bedetected by sensor arrays-printed onto the active micropatch itself,wherein the active micropatch can be fabricated/constructed on aflexible/stretchable substrate (e.g., manufactured by MC10 company).

An active micropatch can be utilized to deliver sildenafil.

An active micropatch can be utilized to deliver testosterone.

An active micropatch can be utilized to deliver luric acid and/or anisolated active protein from the Propionibacterium acnes phages fortreatment against acne.

An active micropatch can be utilized to deliver rivastigmine fortreatment against Alzheimer's disease.

An active micropatch can be utilized to deliver rotigotine for treatmentagainst Parkinson's disease.

An active micropatch (as a transplant active micropatch) can be utilizedto deliver insulin-producing stem cells (by manipulating both the Wntand Notch signals. Wnt enhances self-renewal of adult pancreatic stemcells and inhibiting Notch signaling increases production of insulin) orcells against Type 1 Diabetes disease. The active micropatch may alsocontain protein and immune suppressing bioactive compounds to allow theinsulin-producing cells/stem cells to successfully graft, survive andfunction within a human body.

β-cell replication is difficult to control in a human body. A decreasein the function of β-cells late in life is the main cause of Type 2Diabetes disease. Betatrophin, a liver hormone stimulates β-cellreplication with remarkable efficiency. An active micropatch can beutilized to deliver betatrophin.

An active micropatch can be utilized to deliver a nanoshell 120decorated with a targeting ligand, wherein the targeting ligand canrecognize/match/bind with adenosine receptors—thus allowing a humanbody's blood-brain barrier to be opened for the passage of the nanoshell120 to deliver oxytocin (“the love hormone”). The oxytocin hormone mayhelp build a long-lasting love.

A constant and low dose of psilocybin can calm the psychologicalturbulence of people afflicted with a number of conditions, includingdepression and alcohol addiction. An active micropatch can be utilizedto deliver a nanoshell 120 decorated with a targeting ligand, whereinthe targeting ligand can recognize/match/bind with adenosinereceptors—thus allowing a human body's blood-brain barrier to be openedfor the passage of the nanoshell 120 to deliver psilocybin.

Bacteria outnumber human cells ten to one. A human body has a complexmolecular network of bacteria.

Bacteria possess genes that can encode beneficial compounds and/ormolecules for a human body.

Furthermore, bacteria communicate/socialize (within similar and/ordissimilar species) via chemical molecular quorum sensing (also known asdiffusion/efficiency sensing).

The quorum sensing is like census-taking. Quorum sensing allows bacteriato communicate using secreted chemical signaling molecules calledautoinducers.

The quorum sensing can collectively regulate gene expressions ofbacteria.

The quorum sensing can collectively regulate good/bad behaviors ofbacteria.

An active micropatch can be utilized to deliver a pro-quorum sensingcompound.

An active micropatch can be utilized to deliver an anti-quorum sensingcompound. Such anti-quorum compounds are called disaccharide derivativesand they mimic a class of natural molecules known as rhamnolipids, whichare produced and secreted by the bacterium itself. Such compounds havethe potential to inhibit horizontal gene transfer, the process by whichbacteria share genetic information, such as the ability to bedrug-resistant.

An active micropatch can be utilized as a passive micropatch to delivermultivalent adhesion molecule 7 (MAM7) to disable/disrupt adhesion ofbacteria.

An active micropatch can be utilized to deliver granulocyte macrophagecolony-simulating factor (GMC-SF), which can reprogram a human body'simmune system to attack the cancer cells.

Active Micropatch of Three-Dimensional Porous Graphene Scaffold/Foam

A three-Dimensional porous graphene scaffold/foam can be synthesized bychemical vapor deposition (CVD) using a Ni foam template. Thethree-dimensional porous graphene scaffold/foam can serve as abiocompatible container, when it is coated with laminin/matrix proteins.

The three-dimensional porous graphene scaffold/foam, as an activemicropatch (e.g., a transdermal patch) can be electrically controlled bypolyaniline (PANi) hydrogel electrodes and a thin-film battery/thin-filmprinted battery/biofuel battery/DNA solar cell.

A biofuel battery has a paste with two carbon nanotubes, wherein onecarbon nanotube is mixed with glucose oxidase and the other carbonnanotube is mixed with glucose and polyphenol oxidase. Current isdelivered to the biofuel battery's circuit via a platinum wire insertedinto the paste. The biofuel battery is wrapped in a biocompatiblematerial to prevent any leaking.

A DNA based solar cell incorporates metal atoms and other chemicals tomimic the efficient mechanisms bacteria used to derive energy from thesunlight.

Silicon/polymer nanowires (about 50 nanometers to 100 nanometers indiameter) for stable electronic sensors are more electrically sensitivethan metal electrodes. These stable electronic sensors can be embeddedin the three-dimensional porous graphene scaffold/foam to monitorelectrical activity—thus enabling how living cells and/or stem cellswould respond to specific bioactive compounds 100 and/or bioactivemolecules 100A.

Example Applications of an Active Micropatch of Three-Dimensional PorousGraphene Scaffold/Foam

Nitric mono oxide (NO) is a short-lived, gaseous signaling free radicalmolecule, produced in cells. Once released into a human body'sbloodstream, it signals in a human body to perform certain functionssuch as vasodilatation opening up the blood vessels and capillaries toincrease blood flow and deliver oxygen and critical nutrients throughouta human body at the time it needs them most.

Controlled amounts of nitric mono oxide gas can be beneficial forhealth. Nitric mono oxide can remain stable and trapped within thethree-dimensional porous graphene scaffold/foam.

The three-dimensional porous graphene scaffold/foam, utilizinggraphene/polyaniline hydrogel electrodes and a thin-filmbattery/thin-film printed battery/biofuel battery/engineered bacteriabattery can act as an active micropatch for nitric mono oxide.

Trapped nitric mono oxide can be released in a controlled manner,utilizing graphene/polyaniline hydrogel electrodes and a thin-filmbattery/thin-film printed battery/biofuel battery/engineered bacteriabattery.

Furthermore, chitosan can be added to the three-dimensional porousgraphene scaffold/foam for increasing an antimicrobial killing action.Controlled amounts of nitric mono oxide gas can be beneficial for woundhealing.

The three-dimensional porous graphene scaffold/foam, utilizinggraphene/polyaniline hydrogel electrodes and a thin-filmbattery/thin-film printed battery/biofuel battery/engineered bacteriabattery, as an active micropatch can deliver adipose-derived stem cells(ADSC) for wound healing.

Furthermore, the three-dimensional porous graphene foam, utilizinggraphene/polyaniline hydrogel electrodes and a thin-filmbattery/thin-film printed battery/biofuel battery/engineered bacteriabattery, as an active micropatch can deliver neural stem cells.

Furthermore, the three-dimensional porous graphene foam, utilizinggraphene/polyaniline hydrogel electrodes and a thin-filmbattery/thin-film printed battery/biofuel battery/engineered bacteriabattery and silicon nanowire sensors, as an active micropatch candeliver neural stem cells with embedded silicon nanowire sensors(configured to monitor specific biochemical functions) and specificbioactive compounds 100 and/or bioactive molecules 100A.

Active Micropatch of Three-Dimensional Porous Graphene Scaffold/FoamCoupled with A Porous Nanomembrane & Nanopump

The three-dimensional porous graphene scaffold/foam can be integratedwith an atomically thick (about 1 nanometer thick) porous nanomembrane(e.g., a carbon nanomembrane), wherein the atomically thick porousnanomembrane is attached on a human body.

The three-dimensional porous graphene scaffold/foam integrated with theatomically thick porous nanomembrane can be activated by a thin-filmbattery/thin-film printed battery/biofuel battery/engineered bacteriabattery coupled with phi29 DNA polymerase enzyme as a nanopump (or as anarray of nanopumps with an array of phi29 DNA polymerase enzymes) todeliver the bioactive compounds 100 and/or bioactive molecules 100Aacross the porous nanomembrane, wherein the atomically thick porouscarbon nanomembrane is attached on a human body.

Active Micropatch of Three-Dimensional Porous Epoxy Scaffold/Foam

A three-dimensional porous epoxy scaffold/foam (e.g., hydrogelscaffold/foam), as an active (implantable) micropatch can serve as abiocompatible container for living cells and/or stem cells and/orbioactive compounds 100 and/or bioactive molecules 100A. Thethree-dimensional porous epoxy scaffold/foam, as an active (implantable)micropatch can be electrically controlled with boron-doped diamondelectrodes and a thin-film battery/thin-film printed battery/biofuelbattery/engineered bacteria battery.

Boron-doped conducting diamond-like material can be grown on a silicondioxide (SiO₂) substrate by chemical vapor deposition at about900-degrees' centigrade. Boron-doped conducting diamond-like materialcan be bonded on a polymer substrate and then lifted off from thesilicon dioxide substrate by hydrofluoric (HF) acid. Thus, a boron-dopedconducting diamond-like material can act as an interface electrode forany biological application.

Silicon/polymer nanowires (about 50 nanometers to 100 nanometers indiameter) for stable electronic sensors are more electrically sensitivethan metal electrodes. These stable electronic sensors can be embeddedin the three-dimensional porous epoxy scaffold/foam to monitorelectrical activity—thus enabling how living cells and/or stem cellswould respond to specific bioactive compounds 100 and/or bioactivemolecules 100A.

Example Applications of an Active Micropatch of Three-Dimensional PorousEpoxy Scaffold/Foam

Nitric mono oxide is a short-lived, gaseous signaling free radicalmolecule, produced in cells. Once released into a human body'sbloodstream, it signals a human body to perform certain functions suchas vasodilatation opening up the blood vessels and capillaries toincrease blood flow and deliver oxygen and critical nutrients throughouta human body at the time it needs them most.

Controlled amounts of nitric mono oxide gas can be beneficial forhealth. Nitric mono oxide can remain stable and trapped within thethree-dimensional porous epoxy scaffold/foam.

The three-dimensional porous epoxy scaffold/foam, utilizing boron-dopeddiamond electrodes and a thin-film battery/thin-film printedbattery/biofuel battery/engineered bacteria battery can act as an activemicropatch. Trapped nitric mono oxide can be released in a controlledmanner, utilizing boron-doped diamond electrodes and thin-filmbattery/thin-film printed battery/biofuel battery/engineered bacteriabattery.

Chitosan can be added to the three-dimensional porous epoxyscaffold/foam for increasing an antimicrobial killing action. Controlledamount of nitric mono oxide gas can be beneficial for wound healing.

Furthermore, the three-dimensional porous epoxy scaffold/foam, utilizingboron-doped diamond electrodes and a thin-film battery/thin-film printedbattery/biofuel battery/engineered bacteria battery, as an activemicropatch can deliver adipose-derived stem cells for wound healing.

Furthermore, the three-dimensional porous epoxy foam, utilizingboron-doped diamond electrodes and a thin-film battery/thin-film printedbattery/biofuel battery/engineered bacteria battery, as an activemicropatch can deliver neural stem cells.

Furthermore, the three-dimensional porous epoxy foam, utilizingboron-doped diamond electrodes, a thin-film battery/thin-film printedbattery/biofuel battery/engineered bacteria battery and silicon nanowiresensors, as an active micropatch can deliver neural stem cells withembedded silicon nanowire sensors (configured to monitor specificbiochemical functions) and specific bioactive compounds 100 and/orbioactive molecules 100A.

Active Micropatch of Three-Dimensional Porous Epoxy Scaffold/FoamCoupled with A Porous Nanomembrane & Nanopump

The three-dimensional porous epoxy scaffold/foam can be integrated withan atomically thick (about 1 nanometer thick) porous nanomembrane (e.g.,a carbon nanomembrane), wherein the atomically thick porous nanomembraneis attached on a human body.

The three-dimensional porous epoxy scaffold/foam integrated with theatomically thick porous nanomembrane can be activated by a thin-filmbattery/thin-film printed battery/biofuel battery/engineered bacteriabattery coupled with phi29 DNA polymerase enzyme as a nanopump (or anarray of nanopumps of phi29 DNA polymerase enzymes) to deliver thebioactive compounds 100 and/or bioactive molecules 100A across theporous nanomembrane, wherein the atomically thick porous nanomembrane isattached on a human body.

Active Micropatch of Three-Dimensional Porous Scaffold/Foam of OtherMaterial Matrix

TABLE 14A Compositions Of A Scaffold Com- Wt % Wt % Wt % Wt % positionsMaterial A Material B Material C Material D 1 80% Hydrogel 20% Chitin 280% Hydrogel 20% Chitosan 3 80% Hydrogel 20% Fibroin 4 80% Hydrogel 10%Chitin 10% Chitosan 5 80% Hydrogel 10% Chitin 10% Fibroin 6 80% Hydrogel10% Chitosan 10% Fibroin 7 80% Hydrogel 10% Chitin 10% PGLA 8 80%Hydrogel 10% Chitosan 10% PGLA 9 80% Hydrogel 10% Fibroin 10% PGLA 1070% Hydrogel 10% Chitin 10% Fibroin 10% PGLA 11 70% Hydrogel 10%Chitosan 10% Fibroin 10% PGLA

TABLE 14B Compositions Of A Scaffold Integrated With Various NanowireField Effect Transistors Com- positions From Integrated With An ArrayTable-14A Of Nanowire Field Effect Transistors 1Nanowire^(P1)/Nanowire^(P2)/Nanowire^(P3)/Nanowire^(z)/Nanowire^(c) 2Nanowire^(P1)/Nanowire^(P2)/Nanowire^(P3)/Nanowire^(z)/Nanowire^(c) 3Nanowire^(P1)/Nanowire^(P2)/Nanowire^(P3)/Nanowire^(z)/Nanowire^(c) 4Nanowire^(P1)/Nanowire^(P2)/Nanowire^(P3)/Nanowire^(z)/Nanowire^(c) 5Nanowire^(P1)/Nanowire^(P2)/Nanowire^(P3)/Nanowire^(z)/Nanowire^(c) 6Nanowire^(P1)/Nanowire^(P2)/Nanowire^(P3)/Nanowire^(z)/Nanowire^(c) 7Nanowire^(P1)/Nanowire^(P2)/Nanowire^(P3)/Nanowire^(z)/Nanowire^(c) 8Nanowire^(P1)/Nanowire^(P2)/Nanowire^(P3)/Nanowire^(z)/Nanowire^(c) 9Nanowire^(P1)/Nanowire^(P2)/Nanowire^(P3)/Nanowire^(z)/Nanowire^(c) 10Nanowire^(P1)/Nanowire^(P2)/Nanowire^(P3)/Nanowire^(z)/Nanowire^(c) 11Nanowire^(P1)/Nanowire^(P2)/Nanowire^(P3)/Nanowire^(z)/Nanowire^(c)

Nanowire^(P1) field effect transistor is a polymer nanowire field effecttransistor (optionally coated with a lipid layer).

Nanowire^(P2) field effect transistor is an engineered protein nanowirefield effect transistor (optionally coated with a lipid layer). Anengineered protein based field effect transistor can befabricated/constructed, utilizing a suitable material decorated onengineered protein (e.g., a three-dimensional ball and spike engineeredprotein-synthesized by a fusion of both Dps and gp5c genes).

Nanowire^(P3) field effect transistor is a proton nanowire field effecttransistor (optionally coated with a lipid layer). A natural biopolymerchitosan/melanin based proton field effect transistor incorporates apolymer substrate as a gate, a gate oxide insulator film, a source metalthin-film and a drain metal thin-film for proton current.

Nanowire^(z) field effect transistor is a zinc oxide wire nanowire fieldeffect transistor (optionally coated with a lipid layer).

Nanowire^(C) field effect transistor is a carbon nanotube nanofiberfield effect transistor (optionally coated with a lipid layer).

Compositions as described in Table-14B can enable merging biology andelectronics to monitor a biological function/parameter of a cell/stemcell.

A three-dimensional porous scaffold/foam of various mixtures asillustrated by Table-14A and Table-14B can be fabricated/constructed,utilizing electrospinning/three-dimensional printing process.

Active Micropatch of Porous Nanofiber Mesh Electrically Connected withNanofiber Field Effect Transistors

A porous nanofiber mesh can be electrically connected with nanofiberfield effect transistors (e.g., polymer field effect transistor/zincoxide field effect transistor) to monitor electrical activity—thusenabling how living cells and/or stem cells would respond to specificbioactive compounds 100 and/or bioactive molecules 100A. Furthermore,the nanofiber field effect transistor can be coated/integrated with alipid layer.

Active Micropatch Integrated with Microelectro-Mechanical-SystemReservoirs & Microneedles

A passive delivery of the bioactive compounds 100 and/or bioactivemolecules 100A is generally limited by low permeability (of thebioactive compounds 100 and/or bioactive molecules 100A) in a biologicaltransport medium.

FIG. 7N illustrates a thin-film 320A attached with amicroelectro-mechanical-system microassembly as 420.

The microelectro-mechanical-system microassembly 420 illustrates themicroelectro-mechanical-system reservoirs 300 with monolithicallyintegrated microneedles 340, utilizing a microflow tube 360.

The microflow tube 360 can be connected to a micropump 380.

The micropump 380 can be powered by an electrical power providingcomponent 400. The electrical power providing component 400 can be athin-film battery/thin-film printed battery/biofuel battery/engineeredbacteria battery.

The microelectro-mechanical-system reservoir 300 can befabricated/constructed, utilizing liquid-crystalpolymers/polyimide/silicon/silk/SU-8 resin/other suitable material.

The microelectro-mechanical-system reservoir 300 can be monolithicallyintegrated with the microneedles 340.

The microneedle 340 is biocompatible and about 450 microns long with aninternal hole-diameter of about 45 microns.

The microneedle 340 can be fabricated/constructed, utilizingliquid-crystal polymers/polyimide/silicon/silk/SU-8 resin/other suitablematerial.

The microneedle 340 can be coated with carbon nanotubes, wherein thecarbon nanotubes are integrated with the enzyme Lysostaphin. Lysostaphinis a natural enzyme, which attacks the bacterial cell wall causing itsslicing and disintegration.

The microneedle 340 can be coated with positively chargeddimethyldecylammonium chitosan methacrylate. The interaction ofpositively charged dimethyldecylammonium chitosan methacrylate with thenegatively charged bacterial cell wall can result in the disintegrationof the bacterial cell wall.

Furthermore, the microneedle 340 can be coated with polyvinyl alcoholintegrated with nitric oxide releasing nanoparticle and/or reactiveoxygen species releasing nanoparticle and/or reactive nitrogen speciesreleasing nanoparticle and/or silver oxide nanoparticle and/or titaniumoxide nanoparticle and/or zinc oxide nanoparticle against bacterialinfection.

Furthermore, the microneedle 340 can be coated with poly(ethyleneglycol)-poly(lactic acid) (PEG-PLA) nanoparticle with silver carbenecomplexes (SCCs) to act as a controlled release system against bacterialinfection.

The microelectro-mechanical-system microassembly is indicated as 420.

Thus, a long-term active micropatch (about 15 millimeters² in area) canbe fabricated/constructed for the delivery of the bioactive compounds100 and/or bioactive molecules 100A from the nanoassembly 120F in themicroelectro-mechanical-system reservoirs 300.

Alternatively, a hydrogel contains up to 99.7% water and 0.3% cellulosepolymers by weight, wherein the polymers are held by cucurbiturils.Cucurbiturils are methylene-linked macrocyclic molecules made ofglycoluril [=C4H2N4O2=] monomers. The oxygen atoms are located along theedges of the band and are tilted inwards, forming a partly enclosedcavity.

The hydrogel can protect the bioactive compounds 100 and/or bioactivemolecules 100A for about six (6) months.

The hydrogel (embedded with the bioactive compounds 100 and/or bioactivemolecules 100A) can be utilized in the microelectro-mechanical-systemreservoirs 300 with the nanoassembly 120F.

The hydrogel (embedded with the bioactive compounds 100 and/or bioactivemolecules 100A) can be utilized in the microelectro-mechanical-systemreservoirs 300 without the nanoassembly 120F.

Bee venom contains a potent toxin called melittin that canindiscriminately poke holes in the double-layered membranes of a virus(e.g., hepatitis B, hepatitis C and HIV). However, large amounts of freemelittin can cause a lot of damage to healthy cells. The nanoshell 120can attack an essential part of the virus' structure. Furthermore,melittin-loaded nanoshell 120 can be also effective in killing cancercells.

The hydrogel embedded with melittin can be utilized in themicroelectro-mechanical-system reservoirs 300 without the nanoassembly120F.

Alternatively, a long-term active micropatch (about 15 millimeters' inarea) can be fabricated/constructed for the delivery of the bioactivecompounds 100 and/or bioactive molecules 100A from the hydrogel(embedded with the bioactive compounds 100 and/or bioactive molecules100A e.g., melitin) in the microelectro-mechanical-system reservoirs300.

Furthermore, the bioactive compounds 100 and/or bioactive molecules 100Acan be utilized directly in the microelectro-mechanical-systemreservoirs 300 without the nanoassembly 120F for a long-term activemicropatch.

Thus, in addition to delivering the bioactive compounds 100 and/orbioactive molecules 100A, utilizing the long-term active micropatch,other bio/health sensors to monitor vital health parameters (e.g., bloodsugar and heart rate) can be integrated with the long-term activemicropatch.

An example of a bio/health sensor integrated with the long-term activemicropatch is in-situ blood sugar measurement. Blood sugar measurementcan involve an electrochemical reaction activated by an enzyme. Glucoseoxidase can convert glucose into hydrogen peroxide and otherchemicals—thus their concentrations can be measured with a miniaturepotentiostat or nanosized potentiostat as a biosensor for calculatingthe glucose level in sweat. Furthermore, the bio/health sensor can beintegrated with an analog signal to a digital signal converter circuit.

Wibree, Bluetooth, Wi-Fi and near-field communication can be integratedwith the long-term active micropatch. Furthermore, ultrathin/bare-dieelectronic components, processor(s), sensors, light emitting diodes,photodetectors on the substrate of the long-term active micropatch canbe flexibly interconnected to detect/measure for example, blood flowdynamics, pressure wave velocity (a measure of blood pressure variation)and level of oxygenation in a human blood. Additionally, by injectingtiny heat pulses, the long-term active micropatch can measure a humanskin's thermal conductivity (related to hydration level). Such substrateof the long-term active micropatch is biocompatible and preferably isflexible/stretchable. Furthermore, thin-film digital/source-gatedtransistor based circuits, as an artificial skin can be integrated withthe long-term active micropatch for on-demand delivery of the bioactivecompounds 100 and/or bioactive molecules 100A.

The long-term active micropatch can be integrated with a bio/healthsensor or a wearable device. Details of a wearable device have beendescribed/disclosed in U.S. Non-Provisional patent application Ser. No.14/999,601 entitled “SYSTEM AND METHOD OF AMBIENT/PERVASIVEUSER/HEALTHCARE EXPERIENCE”, filed on Jun. 1, 2016 and the entirecontents of this US Non-Provisional Patent Application are incorporatedherein.

Thus, the bio/health sensor integrated with the long-term activemicropatch can enable active (actively controlled via closed loopmeasurement) delivery of the bioactive compounds 100 and/or bioactivemolecules 100A, utilizing the long-term active micropatch.

The long-term active micropatch can be placed (attached and/orimplanted) on or in (meaning within) a human body

Example Applications of an Active Micropatch Integrated withMicroelectro-Mechanical-System Reservoirs & Microneedles

NAD is a key molecule that coordinates activities between the cell'snuclear genome and the mitochondrial genome. With aging, levels of NADdecline. Without sufficient NAD, SIRT1 can not keep tabs on HIF-1.Levels of HIF-1 can escalate and begin wreaking havoc on thecross-genome communication. Over time, this loss of communicationreduces the cell's ability to make energy and signs of aging relateddiseases become apparent. By administering an endogenous compound (thatcells can transform into NAD) such as, plasma NADmetabolites-nicotinamide mononucleotide, one could restore cross-genomecommunication, if the endogenous compound was administered early enough,prior to excessive mutation accumulation. 7N can be utilized to deliveran endogenous compound (that cells can transform into NAD) to delayonset of aging related diseases.

7N can be utilized as an active micropatch to deliver multivalentadhesion molecule 7 (MAM7) to disable/disrupt adhesion of bacteria.

7N can be utilized as an active micropatch to deliver a liquid drug(e.g., immunoglobulin).

7N can be utilized as an active micropatch to deliver a liquidnanoemulsified drug.

7N can be utilized as an active micropatch to deliver insulin/longacting insulin/smart insulin.

7N can be utilized as an active micropatch to deliver insulin/longacting insulin/smart insulin from the nanoshell 120. For example, thenanoshell 120 can be made of water-fearing molecules (pointing inward)and water-loving molecules (pointing outward). The nanoshell 120 canencapsulate insulin molecules/long acting insulin molecules/smartinsulin molecules. The external surface of the nanoshell 120 can becoupled with an enzyme to convert glucose into gluconic acid. In thepresence of excess glucose, the enzyme (converting glucose into gluconicacid) creates a lack of oxygen and causes water-loving molecules(pointing outward) to collapse-enabling the delivery of insulin/longacting insulin/smart insulin at a suitable external condition.

In another example, the nanoshell 120 (fabricated/constructed by DNAorigami) can be decorated with an aptamer/engineered riboswitch based(excess) glucose sensor. In the presence of excess glucose, thenanoshell 120 can collapse-enabling the delivery of insulin/long actinginsulin/smart insulin at a suitable external condition.

Smart insulin can be Ins-PBA-F, which can consist of a long-actinginsulin derivative that has a chemical moiety with phenylboronic acidadded at one end. Under normal condition, smart insulin can bind withserum proteins (circulating in blood). In the presence of excessglucose, it can bind with phenylboronic acid to release Ins-PBA-F.

7N can be utilized as an active micropatch to deliver insulin/longacting insulin/smart insulin with leptin.

7N can be utilized as an active micropatch to deliver both insulin andglucagon (which lowers the risk of insulin overdose).

7N can be utilized as an active micropatch to deliver both insulin withleptin and glucagon.

7N can be utilized as an active micropatch to deliver exenatide.

7N can be utilized as an active micropatch to deliver specific microRNA.

7N can be utilized as an active micropatch to deliver specific smallinterfering RNA.

7N can be utilized to deliver granulocyte macrophage colony-simulatingfactor, which can reprogram a human body's immune system to attackcancer cells.

Active Micropatch Integrated with Microelectro-Mechanical-SystemReservoirs & Nanotubes

FIG. 7O illustrates a conducting thin-film 320C attached with themicroelectro-mechanical-system reservoirs 300.

Furthermore, the microelectro-mechanical-system reservoirs 300, withintegrated/bonded nanotubes (e.g., a boron nitride/carbon nanotube or atubular structure fabricated/constructed, utilizing DNA/RNA origamiprocess) 120G, utilizing a microflow tube 360, can be connected to amicropump 380. The microelectro-mechanical-system reservoirsmicroassembly is indicated as 420.1.

The micropump 380 can be powered by an electrical power providingcomponent 400. The electrical power providing component 400 can be athin-film battery/thin-film printed battery/biofuel battery/engineeredbacteria battery.

Thus, a long-term active micropatch (about 15 millimeters² in area) canbe fabricated/constructed for the delivery of the bioactive compounds100 and/or bioactive molecules 100A from the nanoassembly 120F.

Alternatively, a long-term active micropatch (about 15 millimeters² inarea) can be fabricated/constructed for the delivery of the bioactivecompounds 100 and/or bioactive molecules 100A from the hydrogel(embedded with the bioactive compounds 100 and/or bioactive molecules100A) in the microelectro-mechanical-system reservoirs 300.

Furthermore, the bioactive compounds 100 and/or bioactive molecules 100Acan be utilized directly within the microelectro-mechanical-systemreservoirs 300 without the nanoassembly 120F.

The nanotubes 120G can be further integrated/bonded with the porousbottom thin-film 320B.

By applying a voltage (about millivolts from a thin-filmbattery/thin-film printed battery/biofuel battery/engineered bacteriabattery) between 320C and the nanostructure membrane 120G, the bioactivecompounds 100 and/or bioactive molecules 100A can be delivered in avariable quantity according to the required dose/need.

Wibree, Bluetooth, Wi-Fi and near-field communication can be integratedwith 7O. Furthermore, ultrathin/bare-die electronic components,processor(s), sensors, light emitting diodes, photodetectors on thesubstrate of 7O can be flexibly interconnected to detect/measure forexample, blood flow dynamics, pressure wave velocity (a measure of bloodpressure variation) and level of oxygenation in a human blood.Additionally, by injecting tiny heat pulses, 7O can measure a humanskin's thermal conductivity (related to hydration level). Such substrateof 7O is biocompatible and preferably is flexible/stretchable.Furthermore, thin-film digital/source-gated transistor based circuits,as an artificial skin can be integrated with 7O for on-demand deliveryof the bioactive compounds 100 and/or bioactive molecules 100A.

7O can be integrated with a bio/health sensor or a wearable device.Details of a wearable device have been described/disclosed in U.S.Non-Provisional patent application Ser. No. 14/999,601 entitled “SYSTEMAND METHOD OF AMBIENT/PERVASIVE USER/HEALTHCARE EXPERIENCE”, filed onJun. 1, 2016 and the entire contents of this US Non-Provisional PatentApplication are incorporated herein.

7O can be placed (attached and/or implanted) on or in (meaning within) ahuman body.

Example Applications of an Active Micropatch Integrated withMicroelectro-Mechanical-System Reservoirs & Nanotubes

NAD is a key molecule that coordinates activities between the cell'snuclear genome and the mitochondrial genome. With aging, levels of NADdecline. Without sufficient NAD, SIRT1 can not keep tabs on HIF-1.Levels of HIF-1 can escalate and begin wreaking havoc on cross-genomecommunication. Over time, this loss of communication reduces the cell'sability to make energy and signs of aging related diseases becomeapparent. By administering an endogenous compound (that cells cantransform into NAD) such as, plasma NAD metabolites-nicotinamidemononucleotide, one could restore cross-genome communication, if theendogenous compound was administered early enough, prior to excessivemutation accumulation. 7O can be utilized to deliver an endogenouscompound (that cells can transform into NAD) to delay onset of agingrelated diseases.

7O can be utilized as an active micropatch to deliver multivalentadhesion molecule 7 (MAM7) to disable/disrupt adhesion of bacteria.

7O can be utilized as an active micropatch to deliver a liquid drug(e.g., immunoglobulin).

7O can be utilized as an active micropatch to deliver a nanoformulatedliquid drug.

7O can be utilized as an active micropatch to deliver insulin/longacting insulin/smart insulin.

7O can be utilized as an active micropatch to deliver insulin/longacting insulin/smart insulin from the nanoshell 120. For example, thenanoshell 120 can be made of water-fearing molecules (pointing inward)and water-loving molecules (pointing outward). The nanoshell 120 canencapsulate insulin molecules/long acting insulin molecules/smartinsulin molecules. The external surface of the nanoshell 120 can becoupled with an enzyme to convert glucose into gluconic acid. In thepresence of excess glucose, the enzyme (converting glucose into gluconicacid) creates a lack of oxygen and causes water-loving molecules(pointing outward) to collapse-enabling the delivery of insulin/longacting insulin/smart insulin at a suitable external condition.

In another example, the nanoshell 120 (fabricated/constructed by DNAorigami) can be decorated with an aptamer/engineered riboswitch based(excess) glucose sensor. In the presence of excess glucose, thenanoshell 120 can collapse-enabling the delivery of insulin/long actinginsulin/smart insulin at a suitable external condition.

Smart insulin can be Ins-PBA-F, which can consist of a long-actinginsulin derivative that has a chemical moiety with phenylboronic acidadded at one end. Under normal conditions, smart insulin can bind withserum proteins (circulating in blood). In the presence of excessglucose, it can bind with phenylboronic acid to release Ins-PBA-F.

7O can be utilized as an active micropatch to deliver insulin/longacting insulin/smart insulin with leptin.

7O can be utilized as an active micropatch to deliver both insulin andglucagon (which lowers the risk of insulin overdose).

7O can be utilized as an active micropatch to deliver both insulin withleptin and glucagon.

7O can be utilized as an active micropatch to deliver exenatide.

7O can be utilized as an active micropatch to deliver specific microRNA.

7O can be utilized as an active micropatch to deliver specific smallinterfering RNA.

FIG. 8 illustrates the microelectro-mechanical-system reservoir 300 with120Fs dispersed in a liquid medium. 120Fs can encapsulate/cage thebioactive compounds 100 and/or bioactive molecules 100A.

However, the bioactive compounds 100 and/or bioactive molecules 100A canbe dispersed directly (via a liquid medium) in themicroelectro-mechanical-system reservoir 300, without the need for 120F.

The microelectro-mechanical-system reservoir 300 is about 1 millimeterin total thickness.

The microelectro-mechanical-system reservoir 300 can be monolithicallyintegrated with the microneedle(s) 340 at the bottom surface 300A of themicroelectro-mechanical-system reservoir 300.

The microneedle 340 is biocompatible and about 450 microns long with aninternal hole-diameter of about 45 microns.

The microneedle 340 can be fabricated/constructed, utilizingliquid-crystal polymers/polyimide/silicon/silk/SU-8 resin/other suitablematerial.

The microelectro-mechanical-system reservoir 300 can be connected to amicroflow tube 360, which is connected to a micropump 380.

The micropump 380 can be powered by an electrical power providingcomponent 400. The electrical power providing component 400 can be athin-film battery/thin-film printed battery/biofuel battery/engineeredbacteria battery.

Such a microelectro-mechanical-system biomodule 420 can be utilized toachieve a higher permeability (of the bioactive compounds 100 and/orbioactive molecules 100A) through a biological transport medium forlong-term programmable/active delivery of the bioactive compounds 100and/or bioactive molecules 100A.

Alternatively, a microelectro-mechanical-system biomodule 420 can beutilized to achieve a higher permeability (of the bioactive compounds100 and/or bioactive molecules 100A) through a biological transportmedium for a long-term programmable/active delivery of the bioactivecompounds 100 and/or bioactive molecules 100A, utilizing a hydrogel.

The hydrogel embedded with the bioactive compounds 100 and/or bioactivemolecules 100A can be utilized in the microelectro-mechanical-systemreservoirs 300.

Wibree, Bluetooth, Wi-Fi and near-field communication can be integratedwith the microelectro-mechanical-system biomodule 420. Furthermore,ultrathin/bare-die electronic components, processor(s), sensors, lightemitting diodes, photodetectors with the microelectro-mechanical-systembiomodule 420 can be flexibly interconnected to detect/measure forexample, blood flow dynamics, pressure wave velocity (a measure of bloodpressure variation) and level of oxygenation in a human blood.Additionally, by injecting tiny heat pulses, themicroelectro-mechanical-system biomodule 420 can measure human skin'sthermal conductivity (related to hydration level). Themicroelectro-mechanical-system biomodule 420 is biocompatible andpreferably is flexible/stretchable. Furthermore, thin-filmdigital/source-gated transistor based circuits, as an artificial skincan be integrated with the microelectro-mechanical-system biomodule 420for on-demand delivery of the bioactive compounds 100 and/or bioactivemolecules 100A.

The microelectro-mechanical-system biomodule 420 can be integrated witha bio/health sensor or a wearable device. Details of a wearable devicehave been described/disclosed in U.S. Non-Provisional patent applicationSer. No. 14/999,601 entitled “SYSTEM AND METHOD OF AMBIENT/PERVASIVEUSER/HEALTHCARE EXPERIENCE”, filed on Jun. 1, 2016 and the entirecontents of this US Non-Provisional Patent Application are incorporatedherein.

The microelectro-mechanical-system biomodule 420 can be placed (attachedand/or implanted) on or in (meaning within) a human body.

Array of Fluidic Containers/Zero-Mode Waveguides (ZMG)

A zero-mode waveguide is a fluidic container that guides light into avolume, which is small in all dimensions compared to the wavelength ofthe incident light.

With an exception of a zero-mode waveguide, by way of an example and notby way of any limitation, a fluidic container can generally mean afluidic capillary (including a microcapillary/nanocapillary) or afluidic well (including a microwell/nanowell) or a fluidic cavity(including a microcavity/nanocavity) or a fluidic channel (including amicrochannel/nanochannel or a recessed substrate/surface or a planarsubstrate/surface, utilizing one or more suitable materials (e.g., aninsulator, a semiconductor-including a two-dimensional crystal material(e.g., graphene) and a metal) of suitable thicknesses tocontain/propagate fluid.

Additionally, a fluidic container/zero-mode waveguide can be integratedwith a flow cell (containing an aqueous solution).

It should be noted that a multilayer of suitable materials with eachlayer of a specifc material/thickness can enable a metamaterial basedsubstrate. Furthermore, a one-dimensional/two-dimensional periodicordered structure in a multilayer of suitable materials with each layerof a specific material/thickness can enable a photonic crystal basedsubstrate.

Array of Photonic Crystal Cavities Based Optical Diagnostic Biomodulefor Detection of A Disease Specific Biomarker/an Array of DiseaseSpecific Biomarkers

FIG. 9A illustrates an array of photonic crystal cavities 500 basedoptical diagnostic biomodule 700A for detection of a disease specificbiomarker 460 (in a human body's blood/biological fluid 440 which can bepropagated through a fluidic channel 620 to a fluidic cavity 520).

The disease specific biomarker 460 can chemically bind with the diseasespecific biomarker binder 240C, wherein the disease specific biomarkerbinder 240C can chemically bind with the fluorophore 120B on an optionalbiomolecular interface layer 480, within the array of photonic crystalcavities (fabricated/constructed, utilizing both low index materials andhigh index materials) 500.

By way of an example and not by way of any limitation, the diseasespecific biomarker 460 can be a disease predicting biomarker (e.g.,higher concentration of fetuin-A protein in a human body's blood canindicate an increased risk of Diabetes disease or higher lever ofC-reactive protein (CRP) protein or lactate dehydrogenase (LDH) proteinin a human body's blood can indicate an increased risk of heart attackor higher level of carcinoembryonic antigen (CEA) indicate an increasedrisk of heart attack).

An incident light from a microelectro-mechanical-system enabledwavelength tunable surface emitting vertical cavity laser 580 can besplit through an optical beam splitter 560, collimated by a lens 540,absorbed by the fluorophore 120B.

Reference incident emission from the microelectro-mechanical-systemenabled wavelength tunable surface emitting vertical cavity laser 580and the fluorescence emission wavelength can be measured by aspectrophotometer 600.

By way of an example and not by way of any limitation, thespectrophotometer 600 can be an array of charged-coupled detectors(CCD)/echelle gratings baseddemultiplexer/microspectrophotometer-on-a-chip/photonic crystal/planarlightwave circuit based demultiplexer/silicon nanowire waveguide baseddemultiplexer spectrophotometer. The spectrophotometer 600 can also be aquantum dot spectrophotometer, which generally utilizes hundreds ofquantum dot material based filters, wherein each quantum dot materialbased filter is designed for a specific set of wavelengths of light. Thequantum dot filters can be printed onto a thin-film (on top of aphotodetector (e.g., charge-coupled devices)).

700A can be scaled to an array of disease specific biomarkers 460, anarray of disease specific biomarker binders 240C and an array offluorophores 120B with distinct fluorescence emission wavelengths. Adirect correlation exists between the fluorescence emission wavelengthand the diameter of a quantum dot fluorophore.

Microspectrophotometer-On-A-Chip

The penetration depth of photons in silicon depends upon wavelength ofphotons. The shorter wavelength photons can be absorbed in topthin-films, while the longer wavelength photons travel some distance,before they can be absorbed in bottom thin-films.

A pixel of a microspectrophotometer-on-a-chip has vertically stackeddetection material thin-film (e.g., silicon) and wavelength tunableoptical filters (utilizing a combination of non-absorbing dielectricthin-films and resistor thin-films configured with thermo-opticsemiconductor thin-films).

A two-dimensional array of the pixels can constitute amicrospectrophotometer-on-a-chip, as the spectrophotometer 600.

Alternatively, the spectrophotometer 600 can be based on a cascadedconfiguration of coarse arrayed waveguide gratings coupler (AWG), finearrayed waveguide gratings coupler and an array of photodetectors.Alternatively, the spectrophotometer 600 can be based on a cascadedconfiguration of coarse arrayed waveguide gratings coupler, fine arrayedwaveguide gratings coupler, an array of ring-resonators and an array ofphotodetectors.

However, an ultra-compact spectrophotometer (as the spectrophotometer600) can be realized, by utilizing photonic crystal (PC) based coarsearrayed waveguide gratings coupler and photonic crystal based finearrayed waveguide gratings coupler.

Microelectro-Mechanical-System Biomodule to Draw/Propagate Blood

FIG. 9B illustrates a microelectro-mechanical-system biomodule 700B todraw blood/biological fluid 440 from a human, utilizing a microneedle340, which can be monolithically integrated with a micromachined(voltage deflectable) membrane 660, a membrane sensor 680 and a fluidicchannel 620.

The microneedle 340 can be electrically powered and programmed to draw ahuman's blood/biological fluid 440 at a periodic interval of time.

Furthermore, the microelectro-mechanical-system biomodule 700B caninclude an array of microneedles 340, an array of micromachinedmembranes 660, an array of membrane sensors 680 and an array of fluidicchannels 620.

Furthermore, an array of fluidic channels 620 can be placed onto anarray of precise silicon/ceramic v-grooves 640.

The array of precise silicon/ceramic v-grooves 640 can be enclosedwithin a precisely machined connector (not shown in FIG. 9B).

The precisely machined connector can be attached precisely/detached fromthe microelectro-mechanical-system biomodule for drawing/propagating ahuman body's blood/biological fluid 440.

Array of Photonic Crystal Cavities Based Integrated Optical DiagnosticBiomodule for Detection of a Disease Specific Biomarker/an Array ofDisease Specific Biomarkers

FIG. 9C illustrates an array of photonic crystal cavities basedintegrated optical diagnostic biomodule 700.

Stokes Shift to Detect a Disease Specific Biomarker/an Array of DiseaseSpecific Biomarkers

The Stokes Shift is the difference between the absorption wavelength andfluorescence emission wavelength.

FIG. 9D illustrates the Stokes Shift due to binding of a diseasespecific biomarker 460 with a disease specific biomarker binder 240C.

The Stokes Shift can be utilized to detect the presence of a diseasespecific biomarker/an array of disease specific biomarkers.

Array of Fluidic Containers Based Optical Diagnostic Biomodule forDetection of a Disease Specific Biomarker/an Array of Disease SpecificBiomarkers

FIG. 10A illustrates an array of fluidic containers 500A based opticaldiagnostic biomodule 700C for detection of a disease specific biomarker460 (in a human body's blood/biological fluid 440, which can bepropagated through a fluidic channel 620 to a fluidic cavity 520).

The disease specific biomarker 460 can chemically bind with a diseasespecific biomarker binder 240C, wherein the disease specific biomarkerbinder 240C can chemically bind with the fluorophore 120B, on anoptional biomolecular interface layer 480, within the array of fluidiccontainers 500A.

Furthermore, the top optical assembly can be removed to allow a directaccess to fill the array of fluidic containers 500A with a human body'sblood/biological fluid 400.

Furthermore, a particular biological fluid can be considered as goldnanoparticles chemically bonded with DNAzyme (DNAzyme, a synthetic DNAenzyme that can cleave a nucleic acid molecule) in liquid form. When adisease gene is introduced, the DNA can be cleaved from the goldnanoparticles, turning the liquid red in color

The array of fluidic containers 500A is optically transparent to theincident light. The incident light from a microelectro-mechanical-systemenabled wavelength tunable surface emitting vertical cavity laser 580can be collimated by a lens 540, absorbed by the fluorophore 120B.

The fluorophore 120B can exist within each container of fluidiccontainers 500A. The fluorophore 120B can be a dye based fluorophore ora quantum dot fluorophore or a fluorescent protein.

700C can be scaled to an array of disease specific biomarkers 460, anarray of disease specific biomarker binders 240C and an array offluorophores 120B with distinct fluorescence emission wavelengths.

Fluorescence emission can propagate through a first optical filter (notto transmit the incident wavelength from themicroelectro-mechanical-system enabled wavelength tunable surfaceemitting vertical cavity laser 580) 560A, an array of lenses 540A and anarray of second optical filters 560B, then finally be detected by anarray of light detectors 600B.

By way of an example and not by way of any limitation, the lightdetector 600B can be a charge-coupled detector/electron multiplyingcharge-coupled detector (EMCCD)/intensified charge-coupled detector(ICCD)/back illuminated high quantum efficiency complementarymetal-oxide-semiconductor (CMOS) detector/color-complementarymetal-oxide-semiconductor detector, wherein a complementarymetal-oxide-semiconductor detector pixel can be integrated with atransparent polyimide light collecting lens and a color (blue, green andred) selective optical filter.

A color selective optical filter can be a wavelength tunable opticalfilter (utilizing a combination of non-absorbing dielectric thin-filmsand resistor thin-films configured with thermo-optic semiconductorthin-films).

Furthermore, the light detector 600B can be based on a single photondetector(s) (e.g., single photon avalanche diode (SPAD) detector). Asingle photon avalanche diode detector is a reverse biased avalanchephotodiode (APD), which is biased above the avalanche breakdown voltagein the Geiger mode.

Microelectro-Mechanical-System Biomodule to Draw/Propagate Blood

FIG. 10B illustrates a microelectro-mechanical-system biomodule 700B todraw blood/biological fluid 440 from a human, utilizing a microneedle340, which can be monolithically integrated with a micromachined(voltage deflectable) membrane 660, a membrane sensor 680 and a fluidicchannel 620.

The microneedle 340 can be electrically powered and programmed to draw ahuman's blood/biological fluid 440 at a periodic interval of time.

Furthermore, the microelectro-mechanical-system biomodule 700B caninclude an array of microneedles 340, an array of micromachinedmembranes 660, an array of membrane sensors 680 and an array of fluidicchannels 620.

Furthermore, an array of fluidic channels 620 can be placed onto anarray of precise silicon/ceramic v-grooves 640.

The array of precise silicon/ceramic v-grooves 640 can be enclosedwithin a precisely machined connector (not shown in FIG. 10B).

The precisely machined connector can be attached precisely/detached fromthe microelectro-mechanical-system biomodule for drawing/propagating ahuman body's blood/biological fluid 440.

Array of Fluidic Containers Based Optical Integrated DiagnosticBiomodule for Detection of a Disease Specific Biomarker/an Array ofDisease Specific Biomarkers

FIG. 10C illustrates an array of fluidic containers based integratedoptical diagnostic biomodule 700.1.

Stokes Shift to Detect a Disease Specific Biomarker/an Array of DiseaseSpecific Biomarkers

The Stokes Shift is the difference between the absorption wavelength andfluorescence emission wavelength.

FIG. 10D illustrates the Stokes Shift due to binding of a diseasespecific biomarker 460 with a disease specific biomarker binder 240C.

The Stokes Shift can be utilized to detect the presence of a diseasespecific biomarker/an array of disease specific biomarkers.

Array of Fluidic Containers Optical Diagnostic Biomodule (Configured bya Camera of A Portable Internet Appliance) for Detection of a DiseaseSpecific Biomarker/an Array of Disease Specific Biomarkers

FIG. 11A illustrates an array of fluidic containers 500A based opticaldiagnostic biomodule 700D, configured by a camera (optionally integratedwith a color image processing algorithm) 600C of the portable internetappliance. This configuration can replace the array of light detectors600B. The camera (of the portable internet appliance) can enablequantitative fluorescence based measurement for a real-time application,utilizing the camera as a photodetector and the portable internetappliance's microprocessor. Furthermore, A surface plasmon enhancedfluorescence microscope (detecting less than 100 fluorophores perdiffraction limited spot) can be realized by utilizing the camera of theportable internet appliance and Kretschmann illumination configuration,where a linearly polarized laser beam (filtered by a linear polarizer)optically excites an ultra thin-film (e.g., 30 nanometers) coatedfluidic container (e.g., a planar quartz substrate) through a glassprism at an illumination angle of about 58 degrees angle.

Furthermore, the top optical assembly can be removed to allow a directaccess to fill the array of fluidic containers 500A with a human body'sblood/biological fluid 440.

700D can be scaled to an array of disease specific biomarkers 460, anarray of disease specific biomarker binders 240C and an array offluorophores 120B with distinct fluorescence emission wavelengths.

Microelectro-Mechanical-System Biomodule to Draw/Propagate Blood

FIG. 11B illustrates a microelectro-mechanical-system biomodule 700B todraw blood/biological fluid 440 from a human, utilizing a microneedle340, which can be monolithically integrated with a micromachined(voltage deflectable) membrane 660, a membrane sensor 680 and a fluidicchannel 620.

The microneedle 340 can be electrically powered and programmed to draw ahuman's blood/biological fluid 440 at a periodic interval of time.

Furthermore, the microelectro-mechanical-system biomodule 700B caninclude an array of microneedles 340, an array of micromachinedmembranes 660, an array of membrane sensors 680 and an array of channels620.

Furthermore, an array of fluidic containers 620 can be placed onto anarray of precise silicon/ceramic v-grooves 640.

The array of precise silicon/ceramic v-grooves 640 can be enclosedwithin a precisely machined connector (not shown in the FIG. 11B).

The precisely machined connector can be attached precisely/detached fromthe microelectro-mechanical-system biomodule for drawing/propagating ahuman body's blood/biological fluid 440.

Array of Fluidic Containers Based Optical Integrated DiagnosticBiomodule (Configured by a Camera of a Portable Internet Appliance) forDetection of a Disease Specific Biomarker/an Array of Disease SpecificBiomarkers

FIG. 11C illustrates an array of fluidic containers based integratedoptical diagnostic biomodule (configured by a camera of the portableinternet appliance) 700.2.

Stokes Shift to Detect a Disease Specific Biomarker/an Array of DiseaseSpecific Biomarkers

The Stokes Shift is the difference between the absorption wavelength andfluorescence emission wavelength.

FIG. 11D illustrates the Stokes Shift due to binding of a geo biomarker460 with a disease specific biomarker binder 240C.

The Stokes Shift can be utilized to detect the presence of a diseasespecific biomarker/an array of disease specific biomarkers.

Array of Fluidic Containers Based Optical Diagnostic Biomodule(Configured by an Array of Optical Fibers & a N×1 Optical Switch) forDetection of a Disease Specific Biomarker/An Array Of Disease SpecificBiomarkers

FIG. 12A illustrates an array of fluidic containers 500A based opticaldiagnostic biomodule 700E, configured by an array of optical fibers 620Aand a N×1 optical switch 600C.

FIG. 12A illustrates an array of fluidic containers based opticaldiagnostic biomodule 700E for detection of a disease specific biomarker(in a human body's blood/biological fluid 440, which can be propagatedthrough a fluidic channel 620 to a fluidic cavity 520).

The disease specific biomarker 460 can chemically bind with a diseasespecific biomarker binder 240C, wherein the disease specific biomarkerbinder 240C can chemically bind with a fluorophore 120B, on an optionalbiomolecular interface layer 480 within the array of fluidic containers500A.

Furthermore, the top optical assembly can be removed to allow directaccess to fill the array of fluidic containers 500A with a human body'sblood/biological fluid.

An incident light from a microelectro-mechanical-system enabledwavelength tunable surface emitting vertical cavity laser 580 can becollimated by a lens 540, absorbed by the fluorophore 120B.

Fluorescence emission can propagate through an array of optical filters(not to transmit the incident wavelength from the laser 580) 560A, anarray of focusing lenses 540B and an array of multi-mode/single-modeoptical fibers 620A to the N×1 multi-mode/single-mode optical switch600C and a spectrophotometer 600.

Furthermore, the array of optical fibers 620A can be attached onto anarray of precise silicon/ceramic v-grooves 640.

The array of optical fibers 620A can be replaced by an array of opticalwaveguides (not shown in FIG. 12A).

N×1 multi-mode/single-mode optical switch 600C can be replaced by anultra-fast N×1 optical switch based on metamaterial (not shown in FIG.12A) to detect the presence of a disease specific biomarker/an array ofdisease specific biomarkers rapidly.

A N×1 multi-mode/single-mode optical switch 600C can be replaced by anultra-fast N×1 optical switch based on (Pb,La)(Zr,Ti)O₃ or LiNbO₃waveguide, when the ultra-fast optical switch is incorporating an (a)input-output 3-dB coupler and (b) a Mach-Zehnder (MZ) modulator.

Alternatively, the N×1 multi-mode/single-mode optical switch 600C can bereplaced by an ultra-fast N×1 optical switch based on vanadium dioxide.A directional coupler (e.g., silicon-on-insulator (SOI) waveguidedirectional coupler) with vanadium dioxide (VO₂) thin-film can beutilized as a fast optical switch, when the vanadium dioxide thin-filmis excited by a mode locked laser (e.g., a mode lockedmicroelectro-mechanical-system tunable vertical cavity surface emittingsemiconductor laser at 1550 nanometers excitation wavelength) with anlight intensity about 2 mJ/cm² to 4 mJ/cm² and a light pulse width ofabout 2 picoseconds to 4 picoseconds) with an integrated focusing lensto focus the excitation light beam to a spot the size of 4.5 microns by4.5 microns. Instead of a focusing lens, curved second order gratingscan be utilized for vertically coupling/focusing onto the vanadiumdioxide thin-film. Furthermore, instead of a classical focusing lens,surface plasmon polariton (SPPs) based nanofocussing waveguide (asillustrated in FIG. 19O) can be utilized for verticallycoupling/focusing onto the vanadium dioxide thin-film. For example, anano-scaled waveguide (rectangular tapered to a point) of an insulatingmaterial, wherein the nano-scaled waveguide is coated/deposited with anultra thin-film of gold can focus a light beam onto an approximate sizeof 25 nanometers by 100 nanometers, due to the surface plasmonpolaritons effect.

Upon excitation by the mode locked laser onto the vanadium dioxidethin-film, the vanadium dioxide thin-film undergoes a semiconductor tometal phase transition/switching and the optical properties of thedirectional coupler can be rapidly changed, such that the optical signal(as the input) at the upper branch of the directional coupler is shifted(as the output) to the lower branch of the directional coupler. Thevanadium dioxide thin-film has an area of about 0.01 microns² to 0.16microns² with thickness in the range of 25 nanometers to 30 nanometers.The vanadium dioxide thin-film is formed about 25 nanometers to 100nanometers away from the straight middle section of the directionalcoupler. The vanadium dioxide thin-film can be fabricated by electronbeam evaporation or laser assisted electron beam evaporation or RFmagnetron sputtering or molecular beam epitaxy or atomic layerdeposition. Alternatively, vanadium dioxide nanoparticles (with diameterin the range of 25 nanometers to 50 nanometers) can be utilized, insteadof the vanadium dioxide thin-film. Furthermore, vanadium(III) oxide(V₂O₃) thin-film/nanoparticles can also be utilized, instead of thevanadium dioxide thin-film/nanoparticles respectively.

In another embodiment, a fast-optical switch-fabricated/constructed as:integrated (a) 3-dB input-output coupler and (b) a Mach-Zehnder typedevice (with electrodes on vanadium dioxide/vanadium(III) oxidethin-film, in intimate proximity to two arms of Mach-Zehnder typedevice) can be activated electrically for a semiconductor to metal phasetransition/switching, without any optical excitation.

The semiconductor to metal phase transition/switching in the vanadiumdioxide/vanadium(III) oxide can be realized below 0.2 picoseconds time,under optical excitation or electrical activation. Thus, thesilicon-on-insulator vanadium dioxide/vanadium(III) oxide siliconphotonics platform can enable a new class of ultrafast silicon photonicdevices (e.g., optical limiters, optical logic gates and opticalmemories).

With the combination of an electrical activation (preferably voltage)and an optical excitation to the vanadium dioxide/vanadium(III) oxidethin-film, a high density optical memory can be realized, whereinoptical excitation is based on an array of vertically aligned nanolasersand surface plasmon polaritons nanofocusing lens. Alternatively,vanadium dioxide/vanadium(III) oxide nanoparticles (about 50 nanometersin diameter) deposited on an array of nanowires lasers/light emittingdiodes can be utilized. For example, vanadium dioxide/vanadium(III)oxide nanoparticles deposited on an array of gallium nitride nanowireslight emitting diodes can be utilized. Furthermore, gallium nitridenanowires light emitting diodes can be electrically powered by zincoxide nanowires. Complementary metal-oxide semiconductor processingelement can be integrated with zinc oxide nanowiresnanogenerator/nanobattery. However, any material with bothsemiconducting and piezoelectric properties can replace galliumnitride-zinc oxide combination.

Faster optical switching time can be obtained by scaling/segmentingvanadium dioxide thin-film to a smaller area and/or by opticalactivation (e.g., ultrashort pulse laser activation) rather than anelectrical activation. Other chemical compositions of vanadium oxide anddoped compositions of vanadium oxide can be utilized to enable a higherperformance optical switch.

Various permutations and combinations of graphene/graphene quantum dotswith vanadium oxide/vanadium oxide quantum dots can be utilized toenable even higher performance optical switch. The process offabricating/constructing graphene layer consists of dispersing agraphene oxide (GO) solution in a micropipette, depositing the solutionlocally and then reducing the graphene oxide to graphene by thermal orchemical treatment.

Furthermore, a particular phase change material-Ag₄In₃Sb₆₇Te₂₆ canswitch between a disordered amorphous phase A and another disorderedamorphous phase B in a sub-picosecond time-scale, when excited bypicosecond electrical pulses (e.g., about 500 kV/cm peak field strengthat a repetition rate of about 30 Hz for about 30 seconds). Such phasechange switching occurs at lower electric field strength/energy leveland can enable an ultra-high speed optical switch (as switching from thedisordered amorphous phase B to the disordered amorphous phase A backrequires an application of a short burst of heat, which can be providedelectrically/optically).

Following permutations and combinations of graphene/graphene quantumdots with Ag₄In₃SboTe₂₆/Ag₄In₃Sb₆₇Te₂₆ thin-film/quantum dots can beutilized to enable even a higher performance optical switch.

The optical switch can be integrated with a log 2N demultiplexer, whichgenerally integrates rectangular shaped periodic frequency filters inseries, wherein the rectangular shaped periodic frequency filters can beformed in one dimensional photonic crystal on a ridge waveguide.

Flip-chip bonding packaging was developed as an alternative towire-bonding. In flip-chip bonding, components are flipped upside-downand placed on an array of solder bumps that form the connection betweencircuitry and package. The optical switch can be packaged, utilizingflip-chip bonding on a precise silicon optical bench substrate.

Fiber can be aligned passively with precise metal alignment pins seatedinto v-grooves on the precise silicon optical bench substrate. Theprecise metal alignment pins are mated with a pluggable optical fiberconnector integrated with a molded plastic lens.

In another embodiment, an ultra-fast N×1 optical switch based onmetamaterial can be fabricated/constructed, utilizing an array ofnanostructured elements, wherein each nanostructured element can beactuated by electrostatic forces on pairs of parallel flexible stringsof nanoscale membrane. Electrically reconfigurable metamaterial elementchanges the transmission and reflection spectra of the metamaterial.

In another embodiment, an ultra-fast N×1 Bose-Einstein condensate basedoptical switch can be realized, utilizing an array ofsingle-mode/multi-mode waveguides on the left-hand side and asingle-mode/multi-mode waveguide on the right-hand side, wherein boththe array of single-mode/multi-mode waveguides on the left-hand side andthe single-mode/multi-mode waveguide on the right-hand side areoptically coupled with polariton Bose-Einstein condensate.

Short-lived room temperature polariton Bose-Einstein condensate can becreated through interaction of a laser light (bouncing back and forthwithin multiple dielectric thin-films) and a luminescent polymericthin-film of about 30 nanometers in thickness. The luminescent polymericthin-film is embedded within multiple dielectric thin-films, wherein themultiple dielectric thin-films is then illuminated from the bottom (ofthe multiple dielectric thin-films, each dielectric thin-film is about40 nanometers in thickness) by a vertical surface emitting laser or anin-plane laser integrated with a suitable 45-degrees angle mirror and afocusing lens.

Furthermore, an ultra-fast N×N Bose-Einstein condensate based opticalswitch can be realized, by utilizing an array of single-mode/multi-modewaveguides on the right-hand side instead of just onesingle-mode/multi-mode waveguide on the right-hand side.

700E can be scaled to an array of disease specific biomarkers 460, anarray of disease specific biomarker binders 240C and an array offluorophores 120B with distinct fluorescence emission wavelengths.

Microelectro-Mechanical-System Biomodule to Draw/Propagate Blood

FIG. 12B illustrates a microelectro-mechanical-system biomodule 700B todraw blood/biological fluid 440 from a human, utilizing the microneedle340, which can be monolithically integrated with a micromachined(voltage deflectable) membrane 660, a membrane sensor 680 and a fluidicchannel 620.

A microneedle 340 can be electrically powered and programmed to draw ahuman's blood/biological fluid 440 at a periodic interval of time.

Furthermore, the microelectro-mechanical-system biomodule 700B caninclude an array of microneedles 340, an array of micromachinedmembranes 660, an array of membrane sensors 680 and an array of fluidicchannels 620.

Furthermore, an array of fluidic channels 620 can be placed onto anarray of precise silicon/ceramic v-grooves 640.

The array of precise silicon/ceramic v-grooves 640 can be enclosedwithin a precisely machined connector (not shown in the FIG. 12B).

The precisely machined connector can be attached precisely/detached fromthe microelectro-mechanical-system biomodule for drawing/propagating ahuman body's blood/biological fluid 440.

Light Incident at Side of an Array of Fluidic Containers

In FIGS. 10A, 11A and 12A light from the microelectro-mechanical-systemenabled wavelength tunable surface emitting vertical cavity laser 580can be incident at the side of the array of fluidic containers 500A.

Light Source Integrated with a Plasmonic Optical Nanoantenna

A plasmonic optical nanoantenna may incorporate two triangular shapedgold configurations, wherein each triangular shaped gold configurationis about 75 nanometers long and facing directly across from each otherin the shape of a miniature bowtie.

The plasmonic optical nanoantenna can squeeze an incident light from themicroelectro-mechanical-system enabled wavelength tunable surfaceemitting vertical cavity laser 580 into 25 nanometers or less gap,separating the two gold triangular configurations—thus resulting in anintense (about thousand times more intense than the light from themicroelectro-mechanical-system enabled wavelength tunable surfaceemitting vertical cavity laser 580) speck of light.

Nanolaser, as a Light Source

For miniaturization, in conjunction with an array of nano-scaled fluidiccontainers, a nanolaser/an array of nanolasers can be utilized, insteadof a microelectro-mechanical-system enabled wavelength tunable surfaceemitting vertical cavity laser/an array ofmicroelectro-mechanical-system enabled wavelength tunable surfaceemitting vertical cavity lasers 580.

By way of an example and not by way of any limitation, the structure ofa metal-insulator-semiconductor-insulator-metal (MISIM) semiconductornanolaser (operating at room temperature) with a rectangularcross-section cavity can consist of a metal organic chemical vapordeposited (MOCVD) rectangular pillar of InP/InGaAs/InP protected on allfour sides of the rectangular pillar with a thin silicon nitrideinsulating layer.

The InP/InGaAs/InP layer stack can form a waveguide, largely confiningthe optical field in a vertical direction. The above rectangular pillaris then encapsulated in silver metal from all four sides as well as fromthe top forming a rectangular cavity in horizontal directions.

The n-contact is silver metal and the p-side contact is connected to anexternal electric source via p-type InGaAsP contact layer underneath therectangular pillar.

Focusing Light onto a Nanosized Spot

A nano-scaled waveguide (rectangular tapered to a point) of aninsulating material, wherein the nano-scaled waveguide iscoated/deposited with an ultra thin-film of gold can focus a light beamonto an approximate size of 25 nanometers by 100 nanometers, due to thesurface plasmon polaritons effect.

Fluorescent or Raman signal light can also propagate in a reversedirection from the point of the nano-scaled tapered device for furtheranalysis.

Light Source Coupled with an Array of Micromirrors

A programmable microelectro-mechanical-system mirror chip can beutilized to divert light of varying wavelengths of the incident lightfrom a microelectro-mechanical-system enabled wavelength tunable surfaceemitting vertical cavity laser 580 at ultra-high speed and withmicrometer-accuracy to the bottom of each fluidic container (for examplein FIG. 12A) from a single light source—thus it will eliminate the needfor an array of microelectro-mechanical-system enabled wavelengthtunable surface emitting vertical cavity lasers 580.

A programmable microelectro-mechanical-system mirror chip may consist ofa large array of individual miniature micromirrors which can each betilted separately and virtually in a continuous way. By controlling thedeflection of all mirrors to distribute the angle of incidence and theintensity of the light with up to 1,000 changes per second over theentire area can be realized.

This particular configuration can enable one to analyze one fluidcontainer at a time—thus reducing any optical cross-talk.

Array of Fluidic Containers Based Optical Integrated DiagnosticBiomodule (Configured by an Array of Optical Fibers & a N×1 OpticalSwitch) for Detection of a Disease Specific Biomarker/an Array ofDisease Specific Biomarkers

FIG. 12C illustrates an array of fluidic containers based integratedoptical diagnostic biomodule 700.3 (configured by an array of opticalfibers 620A and a N×1 optical switch 600C).

Array of Fluidic Containers Based Optical Integrated DiagnosticBiomodule (Configured by an Array of Optical Fibers, a N×1 OpticalSwitch & Multiplexing of Biomarker Binders) for Detection of a DiseaseSpecific Biomarker/an Array of Disease Specific Biomarkers

FIG. 12D illustrates an array of specialized fluidic containers 500A₁,containing a human body's blood/biological fluid 440 with an array ofdisease specific biomarkers 460.

500A₂ is an enclosure for the array of specialized fluidic containers500A₁. 500A₃ is an array of microsized/nanosized mesh tubes. 500A₄ is aremovable holder.

The array of microsized/nanosized mesh tubes 500A₃ can contain abiomarker binder assembly 240C₁ and biomarker binder assembly 240C₂.

FIG. 12E illustrates the biomarker binder assembly 240C₁. 240C₁ canintegrate the biomarker binder 240C, nanoshell 120 and fluorophore120B₁.

The nanoshell 120 can have printed (by electroplating/laser induceddirect printing/soft lithography) metal barcode patterns of alternatingreflective gold/silver/nickel/platinum metal 120B₉ on it.

The stripe width of the metal barcode patterns can be controlled by theamount of current passed during the electroplating process.

The nanoshell 120 can also encapsulate/cage about six (6) quantum dotfluorophores 120B₂, 120B₃, 120B₄, 120B₅, 120B₆ and 120B₇, wherein eachquantum dot fluorophore has a unique fluorescence color based on thediameter of the quantum dot fluorophore.

Furthermore, the intensity of each fluorophore's unique florescenceemission colors can be varied.

The nanoshell 120 can also encapsulate/cage a paramagnetic nanoparticle(e.g., an iron oxide nanoparticle (Fe₃O₄)) 120B₈.

FIG. 12E also illustrates the biomarker binder assembly 240C₂. 240C₂ canintegrate the biomarker binder 240C, nanoshell 120 and nanotube assembly120B₁₁.

The nanotube assembly 120B₁₁ can consist of a nanotube (e.g., a boronnitride/carbon nanotube or a tubular structure fabricated/constructed,utilizing DNA/RNA origami process) 120G. The nanotube 120G canencapsulate/cage at least one quantum dot fluorophore 120B₁ onalternating thin-films of titanium dioxide dielectric (about 15-30nanometers in thickness) 120B₁₂ and metal silver 120B₁₃ (about 5-10nanometers in thickness) on a biochemically functional glass/plasticsubstrate 120B₁₁.

FIG. 12F illustrates the biomarker binder assembly 240C₁, chemicallybonded with a biomarker 460 and an entire biomarker binderassembly-biomarker combination is represented as 460A.

FIG. 12F illustrates the biomarker binder assembly 240C₂, chemicallybonded with a biomarker 460 and an entire biomarker binderassembly-biomarker combination is represented as 460B.

FIG. 12G illustrates an optical diagnostic biomodule 700.4 to determinefluorescence of 460A and 460B upon being magnetically pulled down by anoptically transparent magnetic substrate 120 B₁₄ and then excited by anarray of microelectro-mechanical-system enabled wavelength tunablesurface emitting vertical cavity lasers 580 and collimated by an arrayof lenses 540.

An assembly 640A integrates suitable optical filters, suitable lensesand two (2) optical fibers 620A on precise silicon/ceramic v-grooves.

At one instance, utilizing wavelength λ=λ₁ from themicroelectro-mechanical-system enabled wavelength tunable surfaceemitting vertical cavity laser 580, transmission of wavelength λ=λ₁through a metal barcode pattern, further propagated through a suitableoptical filter, suitable lens and optical fiber 620A is then multiplexedby the N×1 multi-mode/single-mode optical switch 600C and analyzed bythe spectrophotometer 600.

Any suitable image processing software can be utilized to resolve anymisorientated metal barcode pattern.

At another instance, utilizing wavelength λ=λ₂ from themicroelectro-mechanical-system enabled wavelength tunable surfaceemitting vertical cavity laser 580, a fluorescence spectrum of theentire biomarker binder assembly-biomarker combination 460A/460B, ispropagated through a suitable optical filter, suitable lens and opticalfiber 620A, then multiplexed by the N×1 multi-mode/single-mode opticalswitch 600C and analyzed by the spectrophotometer 600.

The array of optical fibers 620A can be replaced by an array of opticalwaveguides (not shown in FIG. 12G).

Furthermore, an array of optical waveguides and lenses can be integrated(by a monolithic and/or a hybrid process) on silica on siliconsubstrate.

One million optical barcodes can be realized, utilizing six (6) uniquefluorescent emission colors and ten (10) intensity levels for eachunique fluorescent emission color.

Furthermore, one million optical barcodes can be also enhanced inconjunction with reflective metal barcode patterns. The reflective metalbarcode patterns indicate a digital barcode.

Up to 2 million or more disease specific biomarkers 460 per specializedfluidic container 500A₁ (or generally referred as, the array of fluidiccontainers) can be identified, utilizing a combination of opticalbarcode multiplexing and metal barcode multiplexing. Data from 2 millionor more disease specific biomarkers 460 can be a large dataset—Big Data.Analysis of Big Data is described in later paragraphs.

For example, considering 19,599 genes in a human body can, in turnproduce about 200,000 types of RNA. Each RNA strand can encode up to200,000 proteins-resulting in 40 billion proteins in a human body.Furthermore, there are millions of patients worldwide—thusmathematical/statistical analysis tools of the Big Data are needed(which are discussed in later paragraphs).

Three-Dimensional Protruded Optical Nanoantenna on a HorizontalPlane/Substrate

FIGS. 12H-12O illustrate eight distinct embodiments (examples) of athree-dimensional protruded optical nanoantenna. FIG. 12H illustrates athree-dimensional protruded optical nanoantenna incorporating anano-scaled star. FIG. 12I illustrates a three-dimensional protrudedoptical nanoantenna incorporating two nano-scaled triangles facing eachother. 12J illustrates a three-dimensional protruded optical nanoantennaincorporating two nano-scaled rods facing each other. FIG. 12Killustrates a three-dimensional protruded optical nanoantennaincorporating a nano-scaled triangle. FIG. 12L illustrates athree-dimensional protruded optical nanoantenna incorporating twonano-scaled spheres facing each other. FIG. 12M illustrates athree-dimensional protruded optical nanoantenna incorporating twonano-scaled v-shapes facing each other. FIG. 12N illustrates athree-dimensional protruded optical nanoantenna incorporating twonano-scaled complex shapes facing each other. FIG. 12N illustrates athree-dimensional protruded optical nanoantenna incorporating twonano-scaled squares with sharp tips facing each other. By way of anexample and not by way of any limitation, a three-dimensional protrudedoptical nanoantenna should not be confined to the above eight distinctembodiments (examples). A three-dimensional protruded opticalnanoantenna can be fabricated/constructed in thin-film metal (e.g.,aluminum/gold/silver) or thin-film metal nitride. Furthermore, thethin-film metal can be polycrystalline or single crystalline instructure. A three-dimensional protruded optical nanoantennafabricated/constructed in single crystalline thin-film metal may giverise to higher performance three-dimensional protruded opticalnanoantenna.

For example, thin-film gold may be a good choice for an opticalexcitation in red wavelength region and thin-film silver may be a goodchoice for an optical excitation in blue-green wavelength region. Thus,a specific choice of material of a three-dimensional protruded opticalnanoantenna can depend on an optical excitation wavelength.

A three-dimensional protruded optical nanoantenna in thin-filmmetal/metal nitride can be coated with a monolayer of a two-dimensionalmaterial (e.g., graphene/graphene oxide/boron nitride (BN)).

Alternatively, a three-dimensional protruded optical nanoantenna can befabricated/constructed on a monolayer of a two-dimensional material(e.g., graphene/graphene oxide/boron nitride) or transition metaldichalcogenide (e.g., tungsten disulfide (WS₂))/carbon 60/conductingnanotube (e.g., carbon nanotube).

It should be noted that non-essential areas of above monolayer beyondthe three-dimensional protruded optical nanoantenna may be etched off toeliminate electrical shorting.

A three-dimensional protruded optical nanoantenna is less than 250nanometers in maximum dimension and the gap of a three-dimensionalprotruded optical nanoantenna (as illustrated in FIGS. 12I, 12J, 12L,12M, 12N and 12O) can be at 25 nanometers or less than 25 nanometers.

It should be noted that a higher performance three-dimensional protrudedoptical nanoantenna can be realized, if the gap of a three-dimensionalprotruded optical nanoantenna (as illustrated in FIGS. 12I, 12J, 12L,12M, 12N and 12O) is less than 25 nanometers and/or the height of athree-dimensional protruded optical nanoantenna (as illustrated in FIGS.12I, 12J, 12L, 12M, 12N and 12O) can be increased (e.g., 30 nanometers)with respect to a substrate (e.g., a quartz substrate) by etching intothe substrate.

Furthermore, three-dimensional protruded optical nanoantennas can bealso embedded with a supported phospholipid membrane (phospholipidmembrane is fluid at room temperature). This can enable mobile moleculesof interest within the bilayer membrane to enter the hot-spot regions ofthe three-dimensional protruded optical nanoantennas via diffusion.

Nano-Scaled Lithography

Helium ion beam lithography (HIBL) on hydrogen-silesquioxane (HSQ)resist can be utilized to create a nanoimprinting lithography (NIL)template. Then, followed by development of hydrogen-silesquioxane resistand surface treatment of anti-sticking layer on hydrogen-silesquioxane.The nanoimprinting lithography template (anti-sticking surface treatedhydrogen-silesquioxane resist) can be utilized to nanoimprint adimension in an ultra violet wavelength (UV) curable nanoimprintingresist at 25 nanometers or less than 25 nanometers. These steps areillustrated in FIG. 12P1.

FIG. 12P2 illustrates an alternative method to fabricate a dimension at25 nanometers or less than 25 nanometers, wherein the etched pattern issubjected to ion (e.g., helium ion) bombardment. Such ion bombardmentcan cause the gaps within the etched pattern to shrink laterally and thereduced gaps within the etched pattern can now be utilized as a mask tofabricate a dimension at 25 nanometers or less than 25 nanometers.

FIG. 12P3 illustrates another alternative method to fabricate adimension at 25 nanometers or less than 25 nanometers, wherein gold (Au)thin-film and a cover metal thin-film are patterned by a first electronbeam (e-beam) lithography and liftoff, followed by reflow/oxidation ofthe cover metal thin-film (e.g., titanium (Ti)/chromium (Cr)) and asecond electron beam lithography and liftoff of gold (Au) thin-film.Further wet etching/removal of the cover metal thin-film can be utilizedto fabricate a dimension at 25 nanometers or less than 25 nanometers.

Additionally, utilizing an ultra thin (e.g., 10 nanometers thick) singlelayer hydrogen-silesquioxane as an electron beam negative resist ordouble layers of hydrogen-silesquioxane negative resist/polymethylmethacrylate (PMMA) positive resist (on a substrate) a dimension at 25nanometers or less than 25 nanometers can be fabricated by electron beamlithography.

ZEP, an electron beam positive resist and calixarene, as an electronbeam negative resist can be utilized to fabricate a dimension at 25nanometers or less than 25 nanometers.

For reducing electron charging due to non-conducting substrate, an ultrathin-layer of conducting polymer or about 30 nanometers of gold can bedeposited on the above electron beam resist.

Positioning Fluorophore (Coupled with a Biomarker Binder) at a DefinedSpot on a Horizontal Plane/Substrate

To significantly enhance the fluorescence signal from the array offluidic containers/zero-mode waveguides, it may be necessary to positionthe fluorophore (coupled with a biomarker binder) at a specified spotwith respect to a substrate.

FIG. 12Q1 illustrates a configuration method 1 to position a fluorophore(coupled with a biomarker binder) on a defined spot of a substrate,wherein the defined spot of such a substrate is defined by an opening ofan electron beam resist. The defined spot is a biotinylated surface. Forexample, a biomarker binder A (e.g., an antibody) can be streptavidinlabeled. The streptavidin labeled biomarker binder A can be attached tothe biotinylated defined spot of such a substrate. In a sandwichstructure, a second biomarker binder B with a fluorophore can beutilized to attach with a biomarker (e.g., antigen).

FIG. 12Q2 illustrates a configuration method 2 to position a fluorophore(coupled with a biomarker binder) on a defined spot of a substrate,wherein the defined spot of such a substrate is defined by an opening ofan electron beam resist. The spot is functionalized with primary amines,using an aminosilane regent and then reacted to create a maleimaideactivated surface for attracting with sulfhydryl groups of the modifiedbiomarker binder A. In a sandwich structure, a second biomarker binder Bwith a fluorophore can be utilized to attach with a biomarker.

FIG. 12Q3 illustrates a configuration method 3 to position a fluorophore(coupled with a biomarker binder) on a defined spot of a substrate,wherein the defined spot of such a substrate is defined by an opening ofan electron beam resist. The spot is functionalized with a molecule α,as shown below:

Then the biomarker binder A is attached with a molecule β, as shownbelow:

In a sandwich structure, a second biomarker binder B with a fluorophorecan be utilized to attach with a biomarker. Alternatively, the moleculeβ chemically coupled with (3-aminopropyl)triethoxysilane molecule toconjugate on the substrate and a molecule, as shown below

can be chemically coupled with the biomarker binder A and thisrearrangement may be necessary for process compatibility with electronbeam lithography.

FIG. 12Q4 illustrates a configuration method 4 to position a fluorophore(coupled with a biomarker binder) on a defined spot of a substrate,wherein the defined spot of such a substrate is defined by an opening ofan electron beam resist. The spot of the substrate is functionalizedwith a DNA/RNA origami surface, which has a diameter of about 100nanometers. A single DNA/RNA strand on a DNA/RNA origami surface can bechemically coupled with a biomarker binder A via a complementary singleDNA/RNA strand on the biomarker binder A. The fabrication/constructionwill be a surface treatment (e.g., by oxygen plasma and/or HMDStreatment), followed by electron beam lithography placement of DNA/RNAorigami surface, which can couple with biomarker binder A.

Alternatively, a DNA/RNA origami surface can be chemically coupled withfunctional (chemical) binding sites (e.g., with maleimide) for abiomarker binder A.

Furthermore, stability of the above DNA/RNA origami surface can beincreased if the DNA/RNA origami surface is dry or in a solutioncontaining 5 millimolar concentration of magnesium ions (from MgCl₂) or500 millimolar concentration of sodium ions (from NaCl₂).

FIG. 12Q5 illustrates a configuration method 5 to position a fluorophore(coupled with a biomarker binder) on a defined spot of a substrate,wherein the defined spot of such a substrate is defined by an opening ofan electron beam resist. Configuration method 5 is similar toconfiguration 4 (as illustrated in FIG. 12Q4), except the above DNA/RNAorigami surface can be chemically coupled by two opposing conductingnanotubes (e.g., single-walled/multi-walled carbon nanotubes or boronnitride nanotubes).

Additionally, above two opposing conducting nanotubes can be replaced bytwo opposing carbon nanospheres or two opposing metal (e.g.,aluminum/gold/silver) nanoparticles or two opposing metal nanorods.

FIG. 12Q6 a configuration method 6 to position a fluorophore (coupledwith a biomarker binder) on a defined spot of a substrate, wherein thedefined spot of such a substrate is defined by an opening of an electronbeam resist. The spot of the substrate is functionalized with a singleDNA/RNA strand, which can be chemically coupled with a biomarker binderA via a complementary single DNA/RNA strand on the biomarker binder A.

Furthermore, about 1 wt % to 2 wt % DNA with CH3(CH2)15N(CH3)3.Cl(hexadecyltrimethylammonium chloride) in butanol solution can beutilized as a direct electron beam lithography resist with functional(chemical) binding sites (e.g., with maleimide) for a biomarker binderA.

In many cases, there can be an electrically isolated metalizedspot/nano-scaled spot instead of a spot of a substrate, wherein theelectrically isolated metalized spot/nano-scaled spot is defined by anopening of an electron beam resist. The electrically isolated metalizedspot/nano-scaled spot can be functionalized with self-assembledmonolayers of 11-mercaptoundecanoic acid, which can be chemicallycoupled with a biomarker binder A.

In many cases, there can be a spot/nano-scaled spot of titanium dioxideinstead of a spot of a substrate, wherein the spot/nano-scaled spot oftitanium dioxide is defined by an opening of an electron beam resist.The spot/nano-scaled spot of titanium dioxide can be functionalized withmonolayers of alkane phosphates, which can be chemically coupled with abiomarker binder A. In a sandwich structure, a second biomarker binder Bwith a fluorophore can be utilized to attach with a biomarker (e.g.,antigen).

Alternatively, there can be a spot/nano-scaled spot of a substrate,wherein other areas can be covered by silicon nitride—thus reducing theneed for two-step electron beam lithography. Alternatively, there can bea spot/nano-scaled spot of aluminum oxide instead of a spot/nano-scaledspot of a substrate, wherein the spot/nano-scaled spot of aluminum oxideis defined by an opening of an electron beam resist. Thespot/nano-scaled spot of aluminum oxide can be functionalized bymonolayers of phosph(on)ate, which can be chemically coupled with abiomarker binder A. In a sandwich structure, a second biomarker binder Bwith a fluorophore can be utilized to attach with a biomarker (e.g.,antigen).

A substrate surface coated with about 10 nanometers thick Nb₂O₅/TiO₂ canbe patterned by electron beam lithography. Such patterned substrate canbe dipped into an aqueous solution of poly(L-lysine) graftedpoly(ethylene glycol) on which a controlled amount of poly(ethyleneglycol) chains are functionalized, which can be chemically coupled witha biomarker binder A. Furthermore, an electron beam resist can beremoved without damaging poly(L-lysine) grafted poly(ethylene glycol)layer. In a sandwich structure, a second biomarker binder B with afluorophore can be utilized to attach with a biomarker.

It should be noted that the second biomarker binder B can be the same asthe first biomarker binder A in some cases.

The height of an antibody can be shortened by either papain/pepsinenzyme.

Furthermore, a single aptamer/wavelength-shifting aptamer/aptamersensor/aptamer beacon/molecular beacon, as a biomarker binder canreplace a relatively taller (e.g., 30 nanometers) sandwich structureincorporating two antibodies, as biomarker binders.

Aptamer Sensor/Molecular Beacon

FIG. 12R1 illustrates an example of an aptamer sensor as a biomarkerbinder, which consists of two chemical components. The first chemicalcomponent is a DNA/RNA based aptamer section as a biomarker binder tochemically couple with a biomarker. The second chemical component is aDNA/RNA based aptamer section to chemically couple with a fluorophore,which is sensitive to its environment. Upon binding of the firstchemical component with a biomarker, the aptamer sensor fluoresces.

FIG. 12R2 illustrates an example of a molecular beacon, as a biomarkerbinder, having self-complementary ends in a stem-loop structure (e.g., ahairpin structure) in its native dark state. Upon binding with abiomarker, a quencher is separated and the molecular beacon fluoresces.

FIG. 12R3 illustrates chemically coupled three distinct biomarkerbinders (e.g., antibody/synthetically designed antibody/aptamer aptamer)A, B and C, wherein the distinct biomarker binder B and the distinctbiomarker binder C are then chemically coupled with a plus ligation armof short sequences of a biological material (e.g., oligonucleotides) anda minus ligation arm of short sequences of a biological material (e.g.,oligonucleotides) respectively. Thus, generating a randomly coiledsingle stranded structure composed of hundreds of copies of a biologicalmaterial, relying on the proximity extension array method (which mayrequire some temperature cycling). Thus, subsequently leading tocovalently hybridization of fluorescent or enzyme-labeled biologicalmaterial. Furthermore, the proximity extension array method can bereplaced by a rolling circle amplification (RCA) method (which mayrequire some temperature cycling). The rolling circle amplificationmethod generates a localized signal via an isothermal amplification of acircle of the biological material. Thus, subsequently leading tocovalently hybridization of fluorescent or enzyme-labeled biologicalmaterial.

Fluorophore (Coupled with a Biomarker Binder) Positioned Relative to aThree-Dimensional Protruded Structure on a Horizontal Plane/Substrate

FIG. 12S1 illustrates positioning a fluorophore (coupled with abiomarker binder) at a defined spot within three-dimensional protrudedcircular gratings (of thin-film metal/thin-film metal nitride) by aconfiguration 1/configuration 2/configuration 3/configuration4/configuration 5/configuration 6. This arrangement is denoted as Ω₁.

Similarly, FIG. 12S2 illustrates positioning a fluorophore (coupled witha biomarker binder) at a defined spot within two opposingthree-dimensional protruded triangles (of thin-film metal/thin-filmmetal nitride) by a configuration 1/configuration 2/configuration3/configuration 4/configuration 5/configuration 6. This arrangement isdenoted as Ω₂.

Similarly, FIG. 12S3 illustrates positioning a fluorophore (coupled witha biomarker binder) at a defined spot within two opposingthree-dimensional protruded conducting nanotubes by a configuration1/configuration 2/configuration 3/configuration 4/configuration5/configuration 6. This arrangement is denoted as Ω₃.

Similarly, FIG. 12S4 illustrates positioning a fluorophore (coupled witha biomarker binder) at a defined spot within two opposingthree-dimensional protruded conducting spheres of a two-dimensionalmaterial by the configuration 1/configuration 2/configuration3/configuration 4/configuration 5/configuration 6. This is denoted asΩ₄.

Similarly, FIG. 12S5 illustrates positioning a fluorophore (coupled witha biomarker binder) at a defined spot on a sharp metalized tip by aconfiguration 1/configuration 2/configuration 3/configuration4/configuration 5/configuration 6. This arrangement is denoted as Ω₅.

Similarly, FIG. 12S6 illustrates positioning a fluorophore (coupled witha biomarker binder) at a defined spot on a sharp metalized tip by aconfiguration 1/configuration 2/configuration 3/configuration4/configuration 5/configuration 6, wherein the sharp metalized tip is ona metal (e.g., aluminum/silver/gold) metal nanoparticle. Thisarrangement is denoted as Ω₆.

Similarly, FIG. 12S7 illustrates positioning a fluorophore (coupled witha biomarker binder) at a defined spot on a sharp metalized tip by aconfiguration 1/configuration 2/configuration 3/configuration4/configuration 5/configuration 6, wherein the sharp metalized tip isplaced within the gap of two opposing three-dimensional protrudedtriangles (of thin-film metal/thin-film metal nitride). This arrangementis denoted as Ω₇. It should be noted that other optical nanoantenna witha gap can also be utilized.

FIG. 12T1 illustrates a nano-scaled open box (having a maximum dimensionless than about 400 nanometers) to enclose/cage a three-dimensionalprotruded optical nanoantenna as illustrated in FIGS. 12H-12O.

FIG. 12T2 illustrates a nano-scaled closed box (having a maximumdimension less than about 400 nanometers) to enclose/cage athree-dimensional protruded optical nanoantenna as illustrated in FIGS.12H-12O.

FIG. 12U1 illustrates a metamaterial structure incorporating alternatingthin-film of metal (of about 15 nanometers in thickness) and thin-filmof insulator/semiconductor (of about 30 nanometers in thickness). Theupper most thin-film of metal is separated by a layer of nanoholes(e.g., of diameter less than 250 nanometers), wherein the nanoholes canact as gratings.

Alternatively, nanoholes can be replaced by two-dimensional gratings asillustrated in FIG. 12U2.

Enhancement of Fluorescent Signal

Light is a wave. Thus, an optical nanoantenna can amplify light waves inthe same way as a television and/or a mobile phone captures radio waves.Two gold nanoparticles (about 40 nanometers in diameter) and afluorophore (e.g., a quantum dot fluorophore) bonded to a syntheticbiological material (e.g., a single stand of DNA) of about 25 nanometersor less in length can act as an optical nanoantenna. The fluorophore canact as a quantum source, supplying the optical nanoantenna with photons.

Generation of Raman Signal

In FIGS. 12A and 12G, the function of the disease specific biomarkerbinder 240C can be enhanced by a dielectric (e.g., silica) sphere (about50 nanometers in diameter).

The dielectric sphere can be encapsulated/caged in a thin metal (e.g.,gold), wherein the thin metal is coupled with the biomarker binder(e.g., a specific antibody/aptamer) 240C to bind with the diseasespecific biomarker 460.

When light from the microelectro-mechanical-system enabled wavelengthtunable surface emitting vertical cavity laser 580 is incident on theabove silica sphere, it can shift a characteristic Raman signal (RamanShift) upon chemically binding with the disease specific biomarker 460.

Measurement of Raman Shift

Measurements of Raman Shift can require a high-performance laser module.But a Raman sensor can utilize the microelectro-mechanical-systemenabled wavelength tunable surface emitting vertical cavity laser 580 toscan over a narrow band of Raman Shift via a suitable wavelength tunableoptical filter.

Surface-Enhanced Raman Scattering/Spectroscopy (SERS)

Surface-Enhanced Resonance Raman Scattering/Spectroscopy (SERRS)

If the bottom of the microsized/nanosized mesh tubes 500A₃ (FIG. 12D) isatomically rough, then the disease specific biomarker 240C can beidentified by surface-enhanced Raman scattering/spectroscopy oralternatively by surface-enhanced Resonance Ramanscattering/spectroscopy.

Electron-beam lithographically patterned and ion beam etched (about) 25nanometers pitch surface gratings of metal thin-film (about 2 to 5nanometers in thickness) deposited by a low-temperature atomic layerdeposition process on porous silicon substrate can be utilized as areproducible atomically rough surface.

Surface-enhanced Raman scattering/spectroscopy is a surface-sensitiveanalytical technique that can enhance Raman scattering by a factor of10¹⁰.

One disadvantage of surface-enhanced Raman scattering/spectroscopy isspectral interpretation. The signal enhancement is so dramatic that evenweak Raman bands (unnoticeable in conventional Ramanscattering/spectroscopy) can appear in surface-enhanced Ramanscattering/spectroscopy.

Some trace contaminants can contribute unwanted peaks insurface-enhanced Raman scattering/spectroscopy. Furthermore, chemicalinteractions with metal surfaces, certain strong peaks (noticeable inconventional Raman scattering/spectroscopy) might not appear insurface-enhanced Raman scattering/spectroscopy.

Because of the above complications in surface-enhanced Ramanscattering/spectroscopy, surface-enhanced Resonance Ramanscattering/spectroscopy can integrate both the surface-enhancement andthe Raman resonance—thus the Raman signal intensity can be as high as10¹⁴ and the Raman spectra can be easier to interpret.

Enhancement of Raman Signal

A Raman nanoprobe (e.g., a single-walled carbon nanotube)encapsulating/caging dye molecules, can enhance enhancement of the Ramansignal, wherein the nanotube can suppress unwanted fluorescence. Thenanotube can be 1 nanometer in diameter and 300 nanometers in length,encapsulating/caging about 500 to 1000 dye molecules.

Addition of Three-Dimensional Protruded Structure(s) in Each FluidicContainer to Enhance Fluorescence Signal

To enhance the fluorescence signal, asingle/one-dimensional/two-dimensional array of three-dimensionalprotruded structures of (a) a single crystalline/polycrystallinethin-film of metal (e.g., aluminum/gold/silver)/metal nitride or (b)two-dimensional material (e.g.,germanene/graphene/phosphorene/silicone/stanene) or (c) conductingnanotubes (e.g., a single-walled/multi-walled carbon nanotube) or (d)sharp tips or (e) Mie-Type resonators can befabricated/constructed/bonded at/near the bottom of each fluidiccontainer of the array of fluidic containers 500A. The thickness of thesingle crystalline/polycrystalline thin-film metal is less than 250nanometers. The geometrical shape or a dimension(s) (e.g., height/depth)of the three-dimensional protruded structure or the pitch/gap of theone-dimensional/two-dimensional array of the three-dimensional protrudedstructures can be varied for maximum enhancement of the fluorescencesignal.

Example: Three-Dimensional Protruded Structure (Atomic Force Microscopy(AFM) Like Sharp Tip)

To enhance the fluorescence signal, asingle/one-dimensional/two-dimensional array of three-dimensionalprotruded atomic force microscopy like sharp tips (e.g., FIG. 12S5/12S6)of a single crystalline/polycrystalline thin-film of metal or asemiconductor can be fabricated/constructed/bonded at/near the bottom ofeach fluidic container of the array of fluidic containers 500A. Thesharpness and/or radius curvature of the three-dimensional protrudedatomic force microscopy like sharp tip and/or pitch/gap/duty cycle ofthe one-dimensional/two-dimensional array of the three-dimensionalprotruded atomic force microscopy like sharp tips can be varied formaximum enhancement of the fluorescence signal

Example: Three-Dimensional Protruded Structure (Grating)

To enhance the fluorescence signal, three-dimensional protruded lineargratings/circular gratings of a single crystalline/polycrystallinethin-film metal/thin-film metal nitride/two-dimensional material can befabricated/constructed/bonded at/near the bottom of each fluidiccontainer of the array of fluidic containers 500A. The geometrical shapeor a dimension(s) (e.g., height/depth) of the three-dimensionalprotruded linear/circular gratings and/or pitch/gap/duty cycle of theone-dimensional/two-dimensional array of the three-dimensional protrudedlinear/circular gratings can be varied for maximum enhancement of thefluorescence signal

Example: Three-Dimensional Protruded Structure (Optical Nanoantenna)

To enhance the fluorescence signal, asingle/one-dimensional/two-dimensional array of three-dimensionalprotruded optical nanoantennas (FIGS. 12H-12O) of a singlecrystalline/polycrystalline thin-film metal/thin-film metalnitride/two-dimensional material can be fabricated/constructed/bondedat/near the bottom of each fluidic container of the array of fluidiccontainers 500A. The typical thickness of the singlecrystalline/polycrystalline thin-film metal is less than 250 nanometers.The geometrical shape or a dimension(s) (e.g., height/depth and/or gap)of the three-dimensional protruded optical nanoantenna and/orpitch/gap/duty cycle of the one-dimensional/two-dimensional array of thethree-dimensional protruded optical nanoantenna can be varied formaximum enhancement of the fluorescence signal. The maximum dimension ofthe three-dimensional optical nanoantenna is less than 250 nanometers.

Example: Three-Dimensional Protruded Structure (Optical Nanoantenna withAtomic Force Microscopy Like Sharp Tip)

To enhance the fluorescence signal, asingle/one-dimensional/two-dimensional array of three-dimensionalprotruded optical nanoantennas of a single crystalline/polycrystallinethin-film metal/thin-film metal nitride/two-dimensional material,wherein each single three-dimensional protruded optical nanoantenna isfabricated/constructed/coupled with an atomic force microscopy likesharp tip e.g., FIG. 12S7 can be fabricated/constructed/bonded at/nearthe bottom of each fluidic container of the array of fluidic containers500A. The typical thickness of the single crystalline/polycrystallinethin-film metal is less than 250 nanometers. The geometrical shape or adimension(s) (e.g., height/depth and/or gap) of the three-dimensionalprotruded optical nanoantenna and/or pitch/gap/duty cycle of theone-dimensional/two-dimensional array of the three-dimensional protrudedoptical nanoantenna can be varied for maximum enhancement of thefluorescence signal. The maximum dimension of the three-dimensionaloptical nanoantenna is less than 250 nanometers.

Example: Three-Dimensional Protruded Structure (Optical Nanoantenna witha Two-Dimensional Material)

As an example, by fabricating/constructing a one atom thick/monolayer ofa two-dimensional material at least on top (a) each nano-scaled triangle(FIG. 12 I), (b) each nano-scaled rod (FIG. 12J), (c) each nano-scaledsphere (FIG. 12L) and (d) each nano-scaled square with sharp tip (FIG.12N), further enhancement of the fluorescence signal can be realizedwith a single/one-dimensional/two-dimensional array of three-dimensionalprotruded optical nanoantennas of a single crystalline/polycrystallinethin-film metal/thin-film metal nitride.

Example: Three-Dimensional Protruded Structure (Optical Nanoantenna witha Thin-Film of Room Temperature Topological Insulator)

A topological insulator is insulator inside or through the bulk, but isconducting around its surfaces/edges. Surface states of a topologicalinsulator are protected by time-reversal symmetry. In contrast to anordinary insulator, such surface states of a topological insulator aredelocalized on the surface and are immune to imperfections in contrastto ordinary insulators.

As an example, by fabricating/constructing an ultra thin-film (e.g.,about 5 nanometers to 50 nanometers in thickness) of a room temperaturetopological insulator (e.g., bismuth selenide (Bi₂Se₃)) at least on topof (a) each nano-scaled triangle (FIG. 12I), (b) each nano-scaled rod(FIG. 12J), (c) each nano-scaled sphere (FIG. 12L) and (d) eachnano-scaled square with sharp tip (FIG. 12N), further enhancement of thefluorescence signal can be realized with asingle/one-dimensional/two-dimensional array of three-dimensionalprotruded optical nanoantennas of a single crystalline/polycrystallinethin-film metal/thin-film metal nitride/two-dimensional material.

Example: Three-Dimensional Protruded Structure (Optical Nanoantenna witha Nanoparticle of Room Temperature Topological Insulator)

As an example, by fabricating/constructing a nanoparticle (e.g., about 2nanometers to 10 nanometers in diameter) of a room temperaturetopological insulator (e.g., bismuth selenide (Bi₂Se₃)) at least on topof (a) each nano-scaled triangle (FIG. 12I), (b) each nano-scaled rod(FIG. 12J), (c) each nano-scaled sphere (FIG. 12L) and (d) eachnano-scaled square with sharp tip (FIG. 12N), further enhancement of thefluorescence signal can be realized with asingle/one-dimensional/two-dimensional array of three-dimensionalprotruded optical nanoantennas of a single crystalline/polycrystallinethin-film metal/thin-film metal nitride/two-dimensional material. Such ananoparticle of a (room temperature) topological insulator of about 10nanometers in diameter can be fabricated/constructed by electron beamlithography/reactive ion etching or colloidal lithography.

Example: Three-Dimensional Protruded Structure (Optical Nanoantenna ofRoom Temperature Topological Insulator)

It should be noted that a room temperature topological insulator canalso replace each nano-scaled triangle (FIG. 12I), (b) each nano-scaledrod (FIG. 12J), (c) each nano-scaled sphere (FIG. 12L) and (d) eachnano-scaled square with sharp tip (FIG. 12N).

Example: Three-Dimensional Protruded Structure (Metamaterial)

To enhance the fluorescence signal, asingle/one-dimensional/two-dimensional array of a three-dimensionalprotruded hyperbolic metamaterial surface (∞₁) (e.g., FIGS. 12U1-12U2)with nanoholes/gratings can be fabricated/constructed/bonded at/near thebottom of each fluidic container of the array of fluidic containers500A. The pitch/gap/duty cycle of the one-dimensional/two-dimensionalarray of the three-dimensional protruded hyperbolic metamaterial surfacewith nanoholes/gratings can be varied for maximum enhancement of thefluorescence signal.

Example: Three-Dimensional Protruded Structure (Photonic Crystal)

A photonic crystal is an artificial periodic arrangement of alow-refractive index dielectric material and a high-refractive indexdielectric material in two/three-dimensions. To enhance the fluorescencesignal or Raman signal, a single/one-dimensional/two-dimensional arrayof photonic crystals can be fabricated/constructed/bonded at/near thebottom of each fluidic container of the array of fluidic containers500A. The refractive indices of the dielectric materials or dimension(e.g., height/depth) of the photonic crystal or the pitch/gap/duty cycleof the one-dimensional/two-dimensional array of photonic can be variedfor maximum enhancement of the fluorescence signal.

One-Dimensional/Two-Dimensional Array of Fluidic Containers forDiagnostic System

The fluidic container can be fabricated/constructed to an approximatevolume of 45 femtoliter to 55 femtoliter (which can have a depth ofabout 3 microns) and the fluidic container can beintegrated/mechanically coupled with a flow cell (containing an aqueoussolution of biological interest).

The side walls of a 45 femtoliter to 55 femtoliter fluidic container canbe passivated/functionalized with a polymeric molecule X (e.g.,polyethylene glycol or polyvinylphosphonic acid (PVPA)). The bottom of a45 femtoliter to 55 femtoliter fluidic container can bepassivated/functionalized with silane/α-X or silane/α-X-biotin, whereinmolecule α is described below:

Addition of Three-Dimensional Protruded Structure(s) in Each Zero-ModeWaveguide to Enhance Fluorescence Signal

The previously discussed embodiments to enhance fluorescence signal,utilizing just one single three-dimensional protruded structure can beapplied for maximum enhancement of the fluorescence signal in eachzero-mode waveguide.

Summary and Applications of Optical Diagnostic Biomodule (FIG. 12V)

FIG. 12V illustrates an embodiment of an optical diagnostic biomodulefor detecting a biomarker or plurality of biomarkers, wherein thebiomarker or the plurality of biomarkers indicate either the presence orabsence of a disease or an infection or a biological agent, or pluralityof diseases or infections or biological agents. The optical diagnosticbiomodule (as in FIG. 12V) can include an array of fluidic containers,wherein each fluidic container of the array of fluidic containers caninclude:

(a) a substrate of the fluidic container can include one or morematerials (or one or more layers of materials, which can be insulatingor semiconducting (including a two-dimensional material) or metallic,but optically suitable/transparent), wherein the fluidic container caninclude one or more first biomarker binders or one or more secondbiomarker binders, wherein more than one the first biomarker binder iseither similar or distinct, wherein more than one the second biomarkerbinder is either similar or distinct, wherein the one first biomarkerbinder is coupled with a first fluorophore (which also includes, but isnot limited to a quantum dot fluorophore/fluorescent protein/noble metalatom nanocluster (a cluster of less than one hundred (100) noble metalatoms (e.g., silver (Ag) atoms)/Mie-type resonator based fluorophore) ora first photoswitchable fluorophore, wherein the fluidic containerincludes one or more three-dimensional protruded structures (they can befabricated/constructed on insulating spots to avoid any electricalshorting), wherein the first fluorophore or the first photoswitchablefluorophore is positioned horizontally relative (e.g., at 25 nanometersor less than 25 nanometers with respect to the one three-dimensionalprotruded structure as in FIG. 12K or alternatively in some cases at 25nanometers or less than 25 nanometers with respect to an open space/gapof the one single three-dimensional protruded structure as in 12L) tothe one three-dimensional protruded structure or the one secondbiomarker binder (or the one second biomarker may be coupled with asecond fluorophore or second photoswitchable fluorophore in some cases)is positioned relative (e.g., at 25 nanometers or less than 25nanometers with respect to the one three-dimensional protruded structureas in FIG. 12K or alternatively in some cases, at 25 nanometers or lessthan 25 nanometers with respect to an open space/gap of the one singlethree-dimensional protruded structure as in 12L) to the onethree-dimensional protruded structure, wherein the dimension or shape ofthe one three-dimensional protruded structure is varied for maximumenhancement of fluorescence emission, wherein more than the onethree-dimensional protruded structure is spaced or arranged in aone-dimensional array or in a two-dimensional array, wherein a pitch ora gap or a duty cycle of the one-dimensional array or thetwo-dimensional array of three-dimensional protruded structures isvaried for maximum enhancement of the fluorescence emission,(b) a light source of a particular wavelength or light sources ofdistinct wavelengths directed at the fluidic container for inducing thefluorescence emission due to the interaction of the one first biomarkerbinder (which is coupled with the fluorophore or the photoswitchablefluorophore) with a biomarker or the one second biomarker binder with abiomarker and(c) a device for detecting the fluorescence emission from the fluidiccontainer.

The substrate of the fluidic container (as in FIG. 12V) can include aperiodic structure of one or more materials.

The fluidic container (as in FIG. 12V) can include one or moresudden/abruptly constricted fluid containers (e.g., fluid channels). Thediameter of the sudden/abruptly constricted fluid container is typicallyabout 25% to 75% smaller than the diameter of cell/stem cell/T cell.During a passage through the (planar) sudden/abruptly constricted fluidcontainer at a high speed, wherein a temporary tiny opening in thecell/stem cell/T cell membrane is formed, without any permanent damageto the cell/stem cell/T cell. This configuration can be utilized to (a)inject bioactive compounds 100 and/or bioactive molecules 100A or (b)the nanoshell 120 to synthesize protein on-demand (as discussed earlier)or (c) the nanoshell 120 to deliver the CRISPR-Cas9 or optogeneticCRISPR-Cas9 system into cell/stem cell/T cell to analyze theeffectiveness of the bioactive compounds 100 and/or bioactive molecules100A and/or synthesized protein on-demand.

The first biomarker binder can be selected from the group consisting of:an isolated antibody, a synthetically designed antibody, an aptamer, awavelength-shifting aptamer and a synthetically designed protein,wherein the synthetically designed protein has a binding site to bindwith the biomarker.

The first biomarker binder can be a nano-scaled synthetically designedbiomolecular circuit, wherein the nano-scaled synthetically designedbiomolecular circuit can include (i) a synthetically designed riboswitchor (ii) a DNA sequence of adenine (A), thymine (T), guanine (G) andcytosine (C) or (iii) a DNA sequence of adenine (A), thymine (T),guanine (G) cytosine (C) and a synthetic molecule or (iv) an RNAsequence or (v) a programmable synthetically designedDNA-targeting-cleaving enzyme (may be coupled with a nanoparticle (ofdiameter less than the nanoshell)) or (vi) a programmable syntheticallydesigned RNA-targeting-cleaving enzyme (may be coupled with ananoparticle (of diameter less than the nanoshell)). The nano-scaledsynthetically designed biomolecular circuit can include a syntheticallydesigned biological logic circuit.

The first biomarker binder can include a nanoshell, wherein thenanoshell is decorated with a cleavable biological material, wherein thecleavable biological material is cleaved from a diseased cell or adecorated diseased cell, wherein the nanoshell may be coupled with ananoparticle (of diameter less than the nanoshell).

The first biomarker binder can include a synthetically designedexosome-specific biomarker binder to couple with a molecule (e.g., smallRNAs, including miRNA, Y-RNA, piwi-RNA and tRNA) of an exosome.

The second biomarker binder can be an aptamer beacon or a molecularbeacon or a noble metal atom nanocluster beacon (a cluster of less thanone hundred (100) noble metal atoms (e.g., silver (Ag) atoms) coupledwith a biological material (e.g., DNA/RNA) fluoresce upon binding with acomplementary biological material (e.g., DNA) or a syntheticallydesigned riboswitch beacon. The aptamer beacon or the molecular beaconor the noble metal atom nanocluster beacon or the synthetically designedriboswitch beacon can include a synthetically designed biological logiccircuit.

The second biomarker binder can be coupled or functionalized (e.g., viaa lipid-functional-spacer construct, which is commercially availablefrom Kode Biotech or via an aptamer) on a nanostructural element (e.g.,a single-walled carbon nanotube/multi-walled carbon nanotube/boronnitride nanotube) of diameter less than 5 nanometers. The secondbiomarker binder may be coupled or functionalized with a syntheticbiological material (e.g., a single stand of DNA), wherein the syntheticbiological material is further coupled with two gold nanoparticles(about 40 nanometers in diameter). The nanostructural element can beelectrically conducting. The nanostructural element can have a pointdefect (e.g., a point defect realized by an electrochemical method, asdiscussed in later paragraphs). Alternatively, the second biomarkerbinder may be coupled or functionalized at the point defect of thenanostructural element, which can be electrically coupled with a fieldeffect transistor (e.g., as in FIG. 13C/13D/13E).

The second biomarker binder can be an aptamer sensor, wherein theaptamer sensor includes a first chemical segment to couple with thebiomarker and a second chemical segment to couple with a secondfluorophore or a second photoswitchable fluorophore.

The second biomarker binder can include both a first isolated antibodyand a second isolated antibody, wherein the first isolated antibody orthe second isolated antibody can be coupled with a second fluorophore ora second photoswitchable fluorophore. The first isolated antibody can bedistinct from the second isolated antibody and they can couple withdistinctly different epitopes.

The second biomarker binder can include both a first syntheticallydesigned antibody and a second synthetically designed antibody, whereinthe first synthetically designed antibody or the second syntheticallydesigned antibody can be coupled with a second fluorophore or a secondphotoswitchable fluorophore. The first synthetically designed antibodycan be distinct from the second synthetically designed antibody and theycan couple with distinctly different epitopes. Furthermore, the firstsynthetically designed antibody or the second synthetically designedantibody can be arranged in three-dimension.

The three-dimensional protruded structure in the fluidic container canbe an optical nanoantenna or a three-dimensional protrudedstructure/construct of a two-dimensional material or a conductingnanotube or a sharp tip or a hyperbolic metamaterial surface. The opengap within the optical nanoantenna is typically 25 nanometers or lessthan 25 nanometers.

The optical nanoantenna can include a room temperature stabletopological insulator or a two-dimensional material or a nanoparticle.The hyperbolic metamaterial surface can include nanoholes or gratings.

It should be noted that the DNA sequence or RNA sequence or programmablesynthetically designed DNA-targeting-cleaving enzyme specificallytargeted to an infection or a biological agent can be attached to amicrosphere/nanosphere. By way of an example and not by way of anylimitation, a biological agent can be Bacillus anthracis/Yersiniapestis/Francisella tularensis/Brucella melitensis/Clostridiumbotulinum/Vaccinia virus/Bacillus thuringiensis kurstaki.

Furthermore, coated/painted/decorated/functionalized cells/disease cellsin-vivo can be realized by a lipid-functional-spacer construct, which iscommercially available from Kode Biotech.

It should be noted that coupling in previous paragraph could meanphysical coupling and/or chemical coupling.

The optical diagnostic biomodule in FIG. 12V can bepassivated/functionalized with:

-   -   first passivating molecules (e.g., polyethylene glycol) on side        walls of each fluidic container and/or,    -   second capturing molecules (e.g., silane-polyethylene glycol        and/or biotin) at or near the bottom of each fluidic container.        The second capturing molecules are capable of capturing (e.g.,        binding/chemically binding/coupling/chemically coupling) with        target molecules of interest for fluorescence and/or,    -   third binding molecules, positioned near or within the open        spaces between the three-dimensional protruded structures (e.g.,        the open space within the single optical nanoantenna, as        illustrated in FIG. 12J) at or near the bottom of each fluidic        container to bind with a biomarker binder within the open space        of the three-dimensional protruded structure.

Each fluidic container can be excited by an incident beam from alaser/laser array of distinct wavelengths. The incident laser can beselected and propagated by a dichroic mirror (or a beam splitter) via anoptical column and objective lens. The optical column can be positionedwith respect to each fluidic container by a precision mechanical stage.Similarly, the fluorescence emission can be propagated by the objectivelens, optical column, dichroic mirror, color splitter and lens. Thefluorescence emission is collected/detected by a photodetector.Furthermore, instead of a laser, a light source can be a two-dimensionalmaterial based light source (e.g., FIG. 12Z1). Utilizing a first laser(from the laser array) and a second laser (from the laser array)simultaneously, a beam of the first laser can be shaped like an opentoroidal shape by altering the optical properties of the pupil plane ofthe objective lens (e.g., integrating diffractive optical elements withobjective lens) and this can enable turning on fluorescence of thefluorophores only in the exact center (spot) of the open toroidal shapedarea (turning off fluorescence of the fluorophores in other areas).Moreover, when the fluorophores are photoswitchable, then a subset ofphotoswitchable fluorophores within the exact center (spot) of the opentoroidal shaped area can be activated—there by significantly enhancingresolution of the fluorescence observation.

The optical diagnostic biomodule in FIG. 12V incorporating the lightsource, wherein the light source can include a coherent light source ora light source, incorporating a two-dimensional material (e.g., FIG.12Z1) for inducing the fluorescence emission in each fluidic container.

The optical diagnostic biomodule in FIG. 12V incorporating the lightsource, wherein the light source can include a first coherent lightsource and a second coherent light source, wherein a beam of the firstcoherent light source is approximately an open toroidal shaped, whereinthe first coherent light source and the second coherent light source areactivated simultaneously for inducing the fluorescence emission on aspot in each fluidic container.

The optical diagnostic biomodule in FIG. 12V incorporating the devicefor detecting fluorescence, wherein the device for detectingfluorescence can include a quantum dot spectrophotometer or acharged-coupled detector or an electron multiplying charged-coupleddetector or a complementary metal-oxide-semiconductor detector or a backilluminated complementary metal-oxide-semiconductor detector or a singlephoton detector for detecting the fluorescence emission from in eachfluidic container.

The optical diagnostic biomodule in FIG. 12V can include an opticalfiber or an optical waveguide, which is optically coupled with eachfluidic container for propagating the fluorescence emission.

The optical diagnostic biomodule in FIG. 12V can include a lens,optically coupled with the optical fiber or the optical waveguide, whichis optically coupled with each fluidic container for propagating thefluorescence emission.

The optical diagnostic biomodule in FIG. 12V can include a N (inputs)×1(output) optical switch, optically coupled with the optical fiber or theoptical waveguide, which is optically coupled with each fluidiccontainer for propagating the fluorescence emission.

Various types of fluidic containers are illustrated in Figures in12W1-12W6.

FIG. 12W1 illustrates a two-dimensional array of recessed surfaces on arigid/flexible substrate (e.g., glass/bendable glass), wherein eachrecessed surface has a two-dimensional array of three-dimensionalprotruded structures (e.g., three-dimensional protruded opticalnanoantennas).

FIG. 12W2 illustrates a two-dimensional array of recessed surfaces on arigid/flexible substrate, wherein each recessed surface has atwo-dimensional array of three-dimensional protrudedstructures-generally represented by Ω_(x) where x=1 (FIG. 12S1 for Ω₁),2 (FIG. 12S2 for Ω₂), 3 (FIG. 12S3 for Ω₃), 4 (FIG. 12S4 for Ω₄), 5(FIG. 12S5 for Ω₅), 6 (FIG. 12S6 for Ω₆) and 7 (FIG. 12S7 for Ω₇).

FIG. 12W3 illustrates a two-dimensional array of recessed surfaces on arigid/flexible substrate, wherein each recessed surface has atwo-dimensional array of three-dimensional protruded structures ofmetamaterial structures.

Furthermore, the one-dimensional array of recessed surfaces can beutilized instead of the two-dimensional array of recessed surfaces.

FIGS. 12W4, 12W5, 12W6 are similar to FIG. 12W1, FIG. 12W2, FIG. 12W3respectively, except the recessed surfaces are replaced by verticallyaligned fluidic containers.

Summary Of Optical Diagnostic Biomodule (FIG. 12X1)

FIG. 12X1 illustrates an embodiment of an optical diagnostic biomodulewhich is similar (including passivation by first molecules, secondmolecules and third molecules) to the optical diagnostic biomodule inFIG. 12V, except it incorporates a zero-mode waveguide, a flow cell. Itshould be noted that all zero-mode waveguides can be optically excited.

It should be noted that coupling in previous paragraph could meanphysical coupling and/or chemical coupling.

Furthermore, coated/painted/decorated/functionalized cells/disease cellsin-vivo can be realized by a lipid-functional-spacer construct, which iscommercially available from Kode Biotech.

The zero-mode waveguide can be wet cleaned with acetone and isopropanol,dried in nitrogen gas and cleaned in oxygen gas or in mixture of 90% (involume) oxygen gas with 10% (in volume) argon gas or in mixture of 90%oxygen gas (in volume)/10% nitrogen gas (in volume) or in mixture ofoxygen gas (90% in volume)/nitrogen gas (5% in volume)/argon gas (5% involume).

The zero-mode waveguide can be passivated/functionalized with:

-   -   first passivating molecules Xs (e.g., polyethylene glycol or        polyvinylphosphonic acid (PVPA)) on the side walls of each        zero-mode waveguide and/or, for example, the polymeric molecule        X in aqueous solution (volume of 50 mL to 250 mL) can be        electrochemically deposited onto the walls of the zero-mode        waveguide by a two-electrode electrochemical cell or a        three-electrode (e.g., working electrode, counter electrode and        reference electrode) electrochemical cell (e.g., manufactured by        Gamry Instruments).    -   second capturing molecules (e.g., silane/α-X or        silane/α-X-biotin at or near the bottom of each zero-mode        waveguide, wherein molecule α is described below:

-   -   The second capturing molecules are capable of capturing (e.g.,        binding/chemically binding/coupling/chemically coupling) with        target molecules for single molecule fluorescence and/or,    -   third binding molecules, positioned near or within the open        spaces between the three-dimensional protruded structures (e.g.,        the open space within the single optical nanoantenna, as        illustrated in FIG. 12J) at or near the bottom of each zero-mode        waveguide to bind with a biomarker binder within the open space        of the three-dimensional protruded structure.

The array of zero-mode waveguides can be optically excited in paralleland the array of zero-mode waveguides should be monitored continuouslyfor detection of fluorescence, as the incorporation of biomarkers into azero-mode waveguide is a random stochastic process. Thus, it requires ahigh-power laser (e.g., 10 W), as each zero-mode waveguide is to beoptically excited close to saturation. Integrating diffractive opticalelements (e.g., binary phase gratings) on the optical (laser) excitationside of the substrate of the array of zero-mode waveguides, theexcitation efficiency of the laser can be increased significantly. Thebinary phase grating is a special case of one-dimensional Damman gratingwith a duty cycle of 50% within a period. However, the substrate of thearray of zero-mode waveguides needs to be thinner (e.g., 25 microns to50 microns) for a depth of binary phase grating at a range of 500nanometers, while the grating pitch and width of grating teeth can besuitably varied for a particular thickness of the substrate of the arrayof zero-mode waveguides.

All zero-mode waveguides (simultaneously) (or each zero-mode waveguidesequentially) can be excited by an incident beam from a laser/laserarray of distinct wavelengths. The incident laser can be selected andpropagated by a dichroic mirror (or a beam splitter) via an opticalcolumn and objective lens. The optical column can be positioned withrespect to each fluidic container by a precision mechanical stage.Similarly, the fluorescence emission can be propagated by the objectivelens, optical column, dichroic mirror, color splitter and lens. Thefluorescence emission is collected/detected by a photodetector.Furthermore, instead of a laser, a light source can be a two-dimensionalmaterial based light source (e.g., FIG. 12Z1). Utilizing a first laser(from the laser array) and a second laser (from the laser array)simultaneously, a beam of the first laser can be shaped like an opentoroidal shape by altering the optical properties of the pupil plane ofthe objective lens (e.g., integrating diffractive optical elements withobjective lens) and this can enable turning on fluorescence of thefluorophores only in the exact center (spot) of the open toroidal shapedarea (turning off fluorescence of the fluorophores in other areas).Moreover, when the fluorophores are photoswitchable, then a subset ofphotoswitchable fluorophores within the exact center (spot) of the opentoroidal shaped area can be activated—thereby significantly enhancingresolution of the fluorescence observation.

It should be noted that optically exciting each zero-mode waveguidesequentially has an advantage, utilizing an optical nanofiber/opticalnanowaveguide with an optical switch.

The optical diagnostic biomodule as illustrated in FIG. 12X1 can includediffractive optical elements to increase excitation efficiency of thelight source or the array of light sources.

Each fluidic container in the optical diagnostic biomodule in FIG.12V/12X1 can include magnesium acetate. Magnesium acetate can beutilized to increase a tiny amount of a nucleic acid (as a biomarker) inthe plasma, upon temperature cycling by a heating device. Furthermore, ametal alloy slab of Invar (a nickel iron alloy) can be sandwichedbetween the heater and each fluidic container. Additionally, atemperature control circuitry can also be integrated.

The optical diagnostic biomodule in FIG. 12V/12X1 can include amicrofluidic device/nanofluidic device/flow cell. Such amicrofluidic/nanofluidic device can be utilized to reduce or eliminatevarious washing steps (utilizing PBS solution and/or Tween-20) forconsumer applications and separation of plasma from a human's blood.

The optical diagnostic biomodule in FIG. 12V/12X1 can include a deviceor an apparatus to isolate exosomes from a biological fluid and toisolate molecules of the exosomes, wherein the device or the apparatusto isolate the exosomes can include a separator module ofexosomes-attached magnetic beads or a nano-scaled filter to filter theexosome from the biological fluid; as described in detail in laterparagraphs.

Device fabrication of the optical diagnostic biomodule in FIG. 12V/12X1can generally include these steps: (a) fabrication of an array of spots(of one or more three-dimensional protruded structures) on a substrate(e.g., quartz) by electron beam lithography and reactive ion etching,(b) fabrication of an array of photoresist columns (e.g., consideringsuitable geometry for the optical diagnostic biomodule in FIG. 12V/12X1)covering the array of spots, (c) blanket deposition of a suitablematerial (e.g., a metal) of suitable thickness and (d) removal of thesuitable material over the array of photoresist columns.

Bioinformatics analysis of molecular components and proteins by theoptical diagnostic biomodule in 12V/12X1 can generate a large set ofData—Big Data. Analysis of Big Data is described in latter paragraphs.

FIG. 12X2 illustrates an optical nanoantenna (indicated by ∞) in eachzero-mode waveguide of the array of zero-mode waveguides.

FIG. 12X3 illustrates a metamaterial surface (indicated by ∞₁) in eachzero-mode waveguide of the array of zero-mode waveguides, wherein themetamaterial surface is integrated with a two-dimensional array ofnanoholes/gratings.

FIG. 12X4 illustrates a metalized sharp tip (indicated by ∞₂) in eachzero-mode waveguide of the array of zero-mode waveguides.

FIG. 12X5 illustrates details of the metalized sharp tip (indicated by∞₂). The sharp tip is created by wet etching on a thin (e.g., 10 micronsin thickness) silicon substrate with <100> crystal orientation and thesharp tip can be metalized. The top surface of silicon substrate has 2.5nanometers thick silicon dioxide dielectric (by atomic layerdeposition). The metalized sharp tip (indicated by ∞₂) is to enhance thefluorescence emission in each zero-mode waveguide of the array ofzero-mode waveguides.

FIG. 12X6 illustrates a metalized sharp tip integrated with a metalnanoparticle (indicated by ∞₃) in each zero-mode waveguide of the arrayof zero-mode waveguides.

FIG. 12X7 illustrates details of the metalized sharp tip integrated witha metal nanoparticle (indicated by ∞₃). The metalized sharp tipintegrated with the metal nanoparticle indicated by ∞₃) is to enhancethe fluorescence emission in each zero-mode waveguide of the array ofzero-mode waveguides.

FIG. 12X8 illustrates a metalized sharp tip integrated with an opticalnanoantenna (indicated by ∞₄) in each zero-mode waveguide of the arrayof zero-mode waveguides.

FIG. 12X9 illustrates a metalized sharp tip integrated with an opticalnanoantenna (indicated by ∞₄) in each zero-mode waveguide of the arrayof zero-mode waveguides. It should be noted that any optical nanoantennawith a gap can be utilized.

FIG. 12X10 illustrates details of the critical process steps of imprintlithography/nanoimprinting lithography, depending on the dimension to beprinted on a substrate.

In FIG. 12X12, step A is to create a silicon template, step B is todeposit a suitable material, step C is to apply adhesive and peel andstep D is to fabricate/construct an array of zero-modewaveguides/nanoholes.

The embodiment of an optical diagnostic biomodule in FIG. 12Y is similarto 12X1 (including a flow cell), except each fluidic container/zero-modewaveguide has a metalized sharp tip. There are various configurations ofthe metalized sharp tip. Such configurations are previously illustratedin FIG. 12X5, FIG. 12X7 and FIG. 12X9.

The optical diagnostic biomodule in FIG. 12X1 can enable single moleculeDNA sequencing, sensors for interactions between biological moleculesincluding DNA-DNA or protein-protein interactions, enzyme activityassays, metabolomic profiling and biological activity in real-time andwith single-molecule resolution.

12Z1 illustrates a tunable light source. By way of an example and not byway of any limitation, the substrate can be either heavily doped p-typesilicon or n-type silicon. Boron nitride thin-film is deposited bychemical vapor deposition on the above substrate. The thickness of boronnitride is less than 250 nanometers. Two-dimensional surface gratings ofabout or less than 10 nanometers in pitch can be fabricated/constructedin boron nitride thin-film and then followed by deposition of atwo-dimensional material (e.g., graphene). Upon electrical excitation, atwo-dimensional material will emit a visible light. The wavelength ofthe emitted visible light can be tuned by varying strength of electricalexcitation (e.g., voltage).

However, if two-dimensional surface gratings of about 100 nanometers to200 nanometers in pitch can be fabricated/constructed in boron nitridethin-film and followed by deposition of a two-dimensional material(e.g., graphene), then a tunable (by varying strength of electricalexcitation) terahertz emission source can be realized.

The optical diagnostic biomodule as illustrated in FIG. 12X1 or 12Y canbe utilized for detection of a biomarker, a single molecule analysis (byfluorescence emission) and DNA/RNA sequencing for diseases/infections.

For example, a biomarker binder (e.g., a specific monoclonal antibody)targeted for Plasmodium falciparum histidine-rich protein-2 biomarker inthe blood/biological fluid can be used to detect early onset of aspecific type of malaria (infection). Biomarker binders targeted forbiomarkers such as NCAM, CRP, SAP, IP-10, ferritin, TPA, 1-309, and MIGin the blood/biological fluid can be used to detect early onset of aspecific type of tuberculosis (infection).

FIG. 12Z2 illustrates a light source/tunable light source in the visiblespectrum, utilizing a two-dimensional material, wherein atwo-dimensional material surface can be functionalized as a biomarkerbinder. Additionally, utilizing either dip-pen nanolithography (DPN) ormicrochannel cantilever spotting (μCS) on a small area of thetwo-dimensional material/surface can be patterned in nanometerresolution to functionalize as a biomarker binder(s)/biological/chemicalsensor(s). Furthermore, a three-dimensional array of a biomarker bindercan also be utilized to enhance sensitivity to detect a disease.

Furthermore, a particular two-dimensional material-graphene's ability toform chemical bonds can be turned on or tuned off based on what isunderneath graphene. When silicon dioxide is underneath graphene, it isreactive when exposed to certain biomarkers/chemicals. But when boronnitride is underneath graphene, it is not reactive when exposed tocertain biomarkers/chemicals. An array of materials (e.g., an array ofboron nitride and silicon dioxide) underneath graphene can be utilizedby an array of sensors to detect a trace amount of biomarkers/chemicals.

FIG. 12Z3 illustrates a nano optical fiber, which consists of a firstregion of a single mode optical fiber, followed by a secondadiabatically tapered region and a third nano optical fiber region. Thetip of the nano optical fiber can be fabricated/constructed with a flatmirror/spherical mirror/silicon waveguide for efficient opticalcoupling. Instead of bulk optics, an array of nano optical fibers can beutilized as a conduit for the incident and fluorescence light inzero-mode waveguide. Furthermore, the array of nano optical fibers canbe connected to inputs of a N×1 optical switch 600 and the output of theoptical switch can be connected to the detector or a spectrophotometer.This configuration can enable faster analysis.

Terahertz Analysis

Terahertz absorption constants can vary linearly with red blood cellconcentrations in whole blood for quantitative analysis of humanblood/infected blood (e.g., blood infected with malaria parasites).Super paramagnetic nanoparticles/nanobeads functionalized with a diseasespecific biomarker binder can be introduced in human blood/infectedblood to chemically bind/couple with a disease specific biomarker. Superparamagnetic nanoparticles/nanobeads functionalized with a diseasespecific biomarker binder chemically binding/coupling with a diseasespecific biomarker can form a cluster. Thus, magnetic property of humanblood/infected blood can be altered and the altered magnetic property ofhuman blood/infected blood can be analyzed by (a) quantifying refractiveindex and absorption coefficient in terahertz or (b) terahertz timedomain spectroscopy. Furthermore, utilizing terahertz time domainspectroscopy and total internal reflection method, wherein amplitude ofan attenuated total internal reflection of terahertz signal throughhuman skin can increase with an increased glucose concentration in bloodincrease—thus enabling non-invasive real-time measurement of bloodglucose concentration in blood. Terahertz imaging can be also integratedwith a film/nano-composite film to make human skin transparent toterahertz, when a measurement is initiated. This ensures consistentreadings across all people independent of age, skin type and color. Therefractive index and absorption coefficient of cancer (e.g., skin,breast and colon cancer) tissue in terahertz are higher in comparison toa normal tissue due to higher water content and structural changes incancer tissue. Terahertz imaging can be highly sensitive to waterconcentration. Thus, it can help detect an early cancer, before it issensitive to other imaging methods.

Additionally, detection by terahertz imaging can be enhanced byartificial intelligence (including self-learning artificialintelligence), computer vision (including self-learning computervision), data mining, fuzzy/neuro-fuzzy logic, machine vision (includingself-learning machine vision), natural language processing, neuralnetworks (including self-learning neural networks), pattern recognition,reasoning modeling and self-learning (including evidence basedself-learning).

It should be noted that artificial intelligence (including self-learningartificial intelligence), computer vision (including self-learningcomputer vision), data mining, fuzzy/neuro-fuzzy logic, machine vision(including self-learning machine vision) natural language processing,neural networks (including self-learning neural networks), patternrecognition, reasoning modeling and self-learning (including evidencebased self-learning) can be enhanced by quantum computing or quantumcomputing based machine learning.

Terahertz imaging (e.g., terahertz pulse imaging, terahertz time domainspectroscopy and terahertz continuous wave spectroscopy) can be utilizedto render real-time imaging during surgery to avoid cutting off healthytissues and exclude leaving cancer tissues in a patient's body.Terahertz imaging can be also utilized to distinguish between softtissue and hard tissue. Terahertz pulse imaging can be used to providevaluable diagnostic information pertaining to enamel, dentine andcavity. Different types of biomolecules leave distinctive molecularspectral fingerprints in the terahertz region and this property enablesboth in-vitro and in-vivo measurements of small biomolecules. Byobtaining both frequency and time domain information, terahertz imagingcan enhance detection of cancer/inflammation and provide sharper imagingand in-vitrolin-vivo molecular fingerprinting/molecular imaging. Aterahertz camera can enable label-free detection ofreactions/interactions of small molecules with proteins—thus enablinghigh speed non-destructive imaging for drug discovery.

Example Application of Terahertz Analysis & On-Demand In-Situ Deliveryof Insulin

Utilizing terahertz time domain spectroscopy and total internalreflection method, wherein amplitude of an attenuated total internalreflection of terahertz signal of human skin can increase with increasedglucose concentration in blood increase—thus enabling non-invasivereal-time measurement of blood glucose concentrations in blood. Suchprimary data can be utilized to deliver the smart nanoshells 120 s(encapsulating/caging insulin/long acting insulin) from the activemicropatch (e.g., as described in FIG. 7N). These smart nanoshells 120 swill only release encapsulated/caged insulin/long acting insulin, whenthe glucose level in blood is high in-situ (a secondary data). Detailsof the smart nanoshells 120 s have been described/disclosed in U.S.Non-Provisional patent application Ser. No. 14/999,601 entitled “SYSTEMAND METHOD OF AMBIENT/PERVASIVE USER/HEALTHCARE EXPERIENCE”, filed onJun. 1, 2016 and the entire contents of this US Non-Provisional PatentApplication are incorporated herein.

For example, the smart nanoshell 120 can be made of water-fearingmolecules (pointing inward) and water-loving molecules (pointingoutward). The smart nanoshell 120 can encapsulate insulin molecules/longacting insulin molecules. The external surface of the smart nanoshellcan be coupled with an enzyme to convert glucose into gluconic acid. Inthe presence of excess glucose, the enzyme (converting glucose intogluconic acid) creates a lack of oxygen and causes water-lovingmolecules (pointing outward) to collapse-enabling the delivery ofinsulin/long acting insulin/smart insulin at a suitable externalcondition.

In another example, the smart nanoshell 120 (fabricated/constructed byDNA origami) can be decorated with an aptamer/engineered riboswitchbased (excess) glucose sensor. In the presence of excess glucose, thesmart nanoshell 120 can collapse-enabling the delivery of insulin/longacting insulin/smart insulin at a suitable external condition.

Smart insulin can be Ins-PBA-F, which can consist of a long-actinginsulin derivative that has a chemical moiety with phenylboronic acidadded at one end. Under normal conditions, smart insulin can bind withserum proteins (circulating in blood). In presence of excess glucose, itcan bind with phenylboronic acid to release Ins-PBA-F.

It should be noted that both terahertz analysis and on-demand in-situdelivery of insulin from the active micropatch (e.g., as described inFIG. 7N) can be integrated with a bio/health sensor or a wearabledevice. Details of a wearable device have been described/disclosed inU.S. Non-Provisional patent application Ser. No. 14/999,601 entitled“SYSTEM AND METHOD OF AMBIENT/PERVASIVE USER/HEALTHCARE EXPERIENCE”,filed on Jun. 1, 2016 and the entire contents of this US Non-ProvisionalPatent Application are incorporated herein.

Integration of Two-Dimensional Material Based Light Source withNegatively Charged Atomic Nitrogen Vacancy (NV) Color Center(s) inDiamond

Negatively charged atomic nitrogen vacancy color centers are pointdefects in a diamond lattice with unique properties in ultra sensitivehigh resolution magnetometry. Although a single (negatively charged)nitrogen vacancy color center in a diamond lattice is useful for highspatial resolution, highest sensitivity can be realized, by utilizing adiamond lattice incorporating many atomic (negatively charged) nitrogenvacancy color centers. A single (negatively charged) nitrogen vacancycolor center can carry a spin that is very sensitive to magnetic fieldsowing to the Zeeman-Effect and the optical rate of emission depends onthe single (negatively charged) nitrogen vacancy color center's spinstate. The (negatively charged) nitrogen vacancy color center can behighly spin polarized via laser irradiation. It can exhibitextraordinarily long coherence times at room temperature (about 1millisecond in Carbon 12 enriched sample).

In order to create (negatively charged) nitrogen vacancy color centersin a diamond lattice, a nitrogen containing crystal can be irradiatedwith high-energy electrons. After irradiation, the crystal containsvacancies that migrate towards nitrogen atoms forming (negativelycharged) nitrogen vacancy color centers in a diamond lattice.

A diamond substrate with (negatively charged) nitrogen vacancy colorcenters just below (within a few nanometers) the top surface can befabricated/constructed. The diamond substrate can be integrated(fabricated/constructed) with a microwave stripline for microwaveexcitation (e.g., at 2.869 GHz). Alternatively, microwave excitation canbe applied via an antenna.

A biological material with a magnetic property/spin can be placed on topof the diamond substrate (integrated with the microwave stripline) with(negatively charged) nitrogen vacancy color centers just below (within afew nanometers) the top surface.

Furthermore, the diamond substrate (with the biological material with amagnetic property/spin) can be placed on top of the two-dimensionalmaterial based light source (as discussed in previous paragraphs) forexcitation at a suitable wavelength (e.g., at 532 nanometers) andred-shifted fluorescence emission (fluoresce in a manner proportional tothe strength of the biological material's own magnetic field) inwavelength range of 600 to 800 nanometers can be detected by anavalanche photodetector/single photon detector. Microwave excitation isamplitude modulated and changes to red-shifted fluorescence emission aremeasured in conjunction with (a) microwave modulation and (b) appliedmagnetic field. Thus, red-shifted fluorescence emission can be used tomap minute magnetism of the biological material.

Furthermore, a light source (e.g., a light emitting diode/laser) of asuitable optical intensity can replace the two-dimensional materialbased light source.

Additionally, a pair of bias magnets and nano positioning stage (e.g., aPZT stage) can be utilized to map the biological material with amagnetic property/spin in high resolution. Alternatively, a laserinstead of the two-dimensional material based light source can beutilized.

For angstrom resolution, a scanning probe (e.g., an atomic forcemicroscope tip) integrated with a single (negatively charged) nitrogenvacancy color center in diamond lattice (just below the surface) can beutilized. Since, a function of a biological material (e.g.,protein/neurons/stem cells) is closely related to its structure, one canestimate/derive a relationship between them.

Example Application for Detection of Malaria

As the malaria parasite consumes a human's red blood cells, it leaves aresidue of insoluble malaria pigment/byproduct hemozoin (heme polymer)in the infected blood. Hemozoin contains iron particles. Hemozoin iseither diamagnetic or super paramagnetic, depending on its oxygenated ordeoxygenated form. But generally, hemozoin is considered superparamagnetic. It has a magnetic permeability constant μ=˜4585 at −20° C.and μ=˜3845 at about +20° C. Under an applied magnetic field, hemozoininduces an optical dichroism, which is a function of its concentration.Precise measurement of this optical dichroism can be utilized to detectmalaria infection.

Alternatively, a diamond substrate (with (negatively charged) nitrogenvacancy color centers just below (within a few nanometers) the topsurface) with hemozoin (in diluted blood of an infected human) on top ofthe diamond substrate can be excited at a wavelength of 532 nanometersand red-shifted fluorescence emission (fluoresce in a mannerproportional to the strength of the hemozoin's own magnetic field) inwavelength range of 600 to 800 nanometers can be detected by a singlephoton detector. The diamond substrate integrated(fabricated/constructed) with a microwave stripline for microwaveexcitation. Additionally, a pair of bias magnets can be utilized. Thus,red-shifted fluorescence emission can be used to map minute magnetism ofhemozoin (hence detection of malaria).

Example Application for Contrast Enhancement in Magnetic ResonanceImaging (MRI) of Cancer

Magnetic resonance imaging can see inside a human body in detail withoutinvasive surgery. A suitable contrast enhancement agent can enhance thisimaging method. For example, the pH of cancer microenvironment is about6.5 to 6.8 (compared to the pH of a human blood which is 7.4). Thenanoshell 120/nanocarrier 160 can be fabricated/constructed to be pHsensitive. The particular pH sensitive nanoshell 120/nanocarrier 160 canencapsulate/cage manganese ions and nanodiamonds. The particular pHsensitive nanoshell 120/nanocarrier 160 can break in a pH range of thecancer microenvironment—thus increasing contrast in magnetic resonanceimaging. Additionally, the nanodiamonds can be conjugated withgadolinium(III), wherein the gadolinium(III) concentration can be variedto realize the highest contrast enhancement in magnetic resonanceimaging and the nanodiamonds can be functionalized with a cancerspecific biomarker binder(s) to bind with a cancer specificbiomarker(s).

Example Application for Contrast Enhancement in Magnetic ResonanceImaging of Cancer & In-Situ Destruction Of Cancer Cells

The particular pH sensitive multifunctional nanoshell 120/nanocarrier160 can encapsulate/cage manganese ions, nanodiamonds and goldnanoparticles. The particular pH sensitive nanoshell 120/nanocarrier 160can break in a pH range of the cancer microenvironment—thus increasingcontrast in magnetic resonance imaging. By heating the goldnanoparticles with a laser of a suitable wavelength, cancer cells can bedestroyed and the subsequent rise in temperature can be reordered in thespin frequency of nanodiamonds. Additionally, the nanodiamonds can beconjugated with gadolinium(III), wherein gadolinium(III) concentrationcan be varied to realize the highest contrast enhancement in magneticresonance imaging and also the nanodiamonds can be functionalized with acancer specific biomarker binder(s) to bind with a cancer specificbiomarker(s). Alternatively/additionally, a magnetic imaging system canbe integrated with a positron emission tomography system to detectcancer cells and a computer controlled focused beam of x-ray and/orproton beam can be utilized to destroy cancer cells.

Example Application for Contrast Enhancement in Hybrid MagneticResonance Imaging & Fluorescence Imaging Of Cancer

The nanoshell 120/nanocarrier 160 can be fabricated/constructed to be pHsensitive. The particular pH sensitive nanoshell 120 canencapsulate/cage manganese ions and fluorescent nanodiamonds (about50-100 nanometers in maximum dimension). The particular pH sensitivenanoshell 120/nanocarrier 160 can break in a pH range of the cancermicroenvironment—thus increasing contrast in magnetic resonance imaging.Additionally, the fluorescent nanodiamonds can be conjugated withgadolinium(III), wherein gadolinium(III) concentration can be varied torealize the highest contrast enhancement in magnetic resonance imagingand also the fluorescent nanodiamonds can be functionalized with acancer specific biomarker binder(s) to bind with a cancer specificbiomarker(s).

In fluorescent nanodiamonds, the nitrogen vacancy color centers in thediamond lattice provide fluorescence. Unlike quantum dots/organic dyes,these nitrogen vacancy color centers do not photobleach/photoblink. Uponlaser excitation, extremely stable fluorescence emission from nitrogenvacancy color centers of fluorescent nanodiamonds can be detected by aphotodetector (e.g., an avalanche photodetector). Thus, enabling hybridmagnetic resonance and fluorescence imaging in a cancer environment.Details of such fluorescence detection have been described/disclosed inU.S. Non-Provisional patent application Ser. No. 14/999,601 entitled“SYSTEM AND METHOD OF AMBIENT/PERVASIVE USER/HEALTHCARE EXPERIENCE”,filed on Jun. 1, 2016 and the entire contents of this US Non-ProvisionalPatent Application are incorporated herein.

Example Application for Contrast Enhancement in Hybrid MagneticResonance Imaging, Fluorescence Imaging of Cancer & In-Situ Destructionof Cancer Cells by Light Excitation

The particular pH sensitive multifunctional nanoshell 120/nanocarrier160 can encapsulate/cage manganese ions, fluorescent nanodiamonds andgold nanoparticles/gold nanorods. The particular pH sensitive nanoshell120/nanocarrier 160 can break in a pH range of the cancermicroenvironment—thus increasing contrast in magnetic resonance imaging.By heating the gold nanoparticles/gold nanorods with a laser source of asuitable wavelength, cancer cells can be destroyed and the subsequentrise in temperature can be reordered in the spin frequency offluorescent nanodiamonds. Additionally, the fluorescent nanodiamonds canbe conjugated with gadolinium(III), wherein the gadolinium(III)concentration can be varied to realize the highest contrast enhancementin magnetic resonance imaging and also the fluorescent nanodiamonds canbe functionalized with a cancer specific biomarker binder(s) to bindwith a cancer specific biomarker(s). Alternatively/additionally, amagnetic imaging system can be co-integrated with a positron emissiontomography system to detect cancer cells and a computer controlledfocused beam of x-ray and/or proton beam can be utilized to destroycancer cells.

Example Application for Contrast Enhancement in Hybrid MagneticResonance Imaging, Fluorescence Imaging of Cancer & In-Situ Destructionof Cancer Cells by Light Excitation

The particular pH sensitive multifunctional nanoshell 120/nanocarrier160 can encapsulate/cage manganese ions, fluorescent nanodiamonds andgold nanoparticles/gold nanorods. A hairpin DNA structure can becovalently conjugated on the surface of gold nanoparticles/gold nanorodsand cancer destroying drug molecules (e.g.,camptothecin/doxorubicin/paclitaxel molecules) can be intercalated intothe adjacent base pairs of hairpin DNA structures. The particular pHsensitive nanoshell 120/nanocarrier 160 can break in a pH range of thecancer microenvironment—thus increasing contrast in magnetic resonanceimaging. Upon visible light excitation (e.g. at 532 nanometers, atplasmonic resonance wavelength of gold nanoparticles/gold nanorods) thegenerated photothermal response assists the rapid release of cancerdestroying drug molecules from the surface of gold nanoparticles/goldnanorods can result in enhanced antitumor activity. Additionally, thefluorescent nanodiamonds can be conjugated with gadolinium(III), whereingadolinium(III) concentrations can be varied to realize the highestcontrast enhancement in magnetic resonance imaging and also thefluorescent nanodiamonds can be functionalized with a cancer specificbiomarker binder(s) to bind with a cancer specific biomarker(s).Alternatively/additionally, a magnetic imaging system can be integratedwith a positron emission tomography system to detect cancer cells and acomputer controlled focused beam of x-ray and/or proton beam can beutilized to destroy cancer cells.

The particular pH sensitive multifunctional nanoshell 120/nanocarrier160 can encapsulate/cage manganese ions, fluorescent nanodiamonds, goldnanoparticles/gold nanorods and upconverting nanoparticles. A hairpinDNA structure can be covalently conjugated on the surface of goldnanoparticles/gold nanorods and cancer destroying drug molecules (e.g.,camptothecin/doxorubicin/paclitaxel molecules) can be intercalated intothe adjacent base pairs of hairpin DNA structures. The particular pHsensitive nanoshell 120/nanocarrier 160 can break in a pH range of thecancer microenvironment—thus increasing contrast in magnetic resonanceimaging. Upon visible light excitation (e.g. at 532 nanometers, atplasmonic resonance wavelength of gold nanoparticles/gold nanorods) thegenerated photothermal response assists the rapid release of cancerdestroying drug molecules from the surface of gold nanoparticles/goldnanorods can result in enhanced antitumor activity. Furthermore, uponinfrared light excitation, the light sensitive upconverting nanoparticlecan generate localized reactive oxygen species to destroy cancer cells.Additionally, the fluorescent nanodiamonds can be conjugated withgadolinium(III), wherein gadolinium(III) concentrations can be varied torealize the highest contrast enhancement in magnetic resonance imagingand also the fluorescent nanodiamonds can be functionalized with acancer specific biomarker binder(s) to bind with a cancer specificbiomarker(s). Alternatively/additionally, a magnetic imaging system canbe integrated with a positron emission tomography system to detectcancer cells and a computer controlled focused beam of x-ray and/orproton beam can be utilized to destroy cancer cells.

By Way of an Example and not by Way of any Limitation, an Exosome as aDisease Specific Biomarker

A disease specific biomarker 460 can indicate the progression of adisease. Exosome (40 nanometers to 100 nanometers in diameter) andmicrovesicle (>100 nanometers to 1000 nanometers in diameter) are smallvesicles that are shed by cells periodically. On an average, eachexosome contains only 1 to 10 RNA molecules, wherein each RNA moleculehas an average of 100 nucleotides. However, taking into account thatexosomes are present in very high numbers in body fluids (typically >10⁹per mL), as a population they are capable of inducing significantbiological effects.

An exosome and/or a microvesicle carry messenger RNAs, micro-RNAs andsignaling proteins. An exosome contains RNAs or other molecules. Cellscommunicate with each other by sending and receiving exosomes—thus anexosome can be viewed as a unit for cell-to-cell biologicalcommunication (molecular Twitter) directly by surface expressed ligandsor transferring molecules from the originating cells. For example,exosomes can carry material from the originating cancer cells tosuppress the immune system and stimulate angiogenesis for the growth ofcancer cells.

An exosome and/or a microvesicle can be isolated from a human body'sblood/biological fluid by ultracentrifugation and filtration. An exosomecan contain many types of molecules such as: small RNAs, includingmiRNA, Y-RNA, piwi-RNA and tRNA. The circulating level, origination andmessage transported by an exosome and/or a microvesicle can be utilizedas a disease specific biomarker 460. A specific microRNA in an exosomeand/or a microvesicle isolated from a disease specific blood can beelevated compared to an exosome and/or a microvesicle isolated fromnon-disease specific blood. Thus, microRNA analysis within an exosomeand/or a microvesicle can be utilized to predict a patient-specificdisease, before any clinical symptoms occur.

Relevant properties of an exosome and/or a microvesicle are size, sizedistribution, density, morphology, composition and zeta potential.Furthermore, an exosome and/or a microvesicle as a disease specificbiomarker can be selectively qualified and/or quantified by a diseasespecific biomarker binder, wherein the disease specific biomarker binderis coupled with a fluorophore (e.g., a quantum dot fluorophore) or aphotoswitchable fluorophore.

By Way of an Example and not by Way of any Limitation, a Glycoprotein asa Disease Specific Biomarker

Elusive glycoprotein can form when a sugar molecule(s) is attached to aprotein. The glycoprotein in the biological fluid/blood can indicate adisease (including a cancer). A nano-scaled polymer can be utilized tochemically couple with a sugar molecule to indentify the glycoprotein.

By Way of an Example and not by Way of any Limitation, EngineeredNanoparticles/Nanosensors Attached with a Disease SpecificEnzyme(s)/Protein(s)/mRNA Fragment(s) as a Disease Specific BiomarkerBinder

Injected engineered nanoparticles/nanosensors in a human body can attachwith a disease specific enzyme(s)/protein(s)/fragment(s) of mRNA(s).Such engineered nanoparticles/nanosensors attached with a diseasespecific enzyme(s)/protein(s)/mRNA(s) fragment(s) can be found inblood/biological fluid. For example, p24-a protein related to HIVinfection and endoproteases enzymes related to various cancers can beidentified as biomarkers.

By Way of an Example and not by Way of any Limitation, an Antibody orAptamer/Aptamer Sensor or Synthetic/Engineered Riboswitch or MolecularBeacon/Riboswitch Beacon as a Disease Specific Biomarker Binder

A disease specific biomarker binder 240C can be a specificantibody/synthetic antibody/aptamer/aptamer beacon/molecularbeacon/synthetic or an engineered riboswitch/synthetic or an engineeredribowitch beacon.

A synthetic antibody is a supramolecular form aptamer componentcontaining one or more functional groups (e.g., amino acids, fattyacids, carbohydrates, small organics and/or metals) into a uniqueorientation. The order and proximity of these functional groups can playa role in enhanced functionalities ranging from higher affinities andspecifities.

There are DNA aptamers or RNA aptamers or XNA aptamers or peptideaptamers. DNA/RNA/XNA aptamers generally consist of short strands ofoligonucleotides. Peptide aptamers generally consist of a short variablepeptide domain, attached at both ends to a protein scaffold.

Furthermore, an aptamer can be a (fluorescence) wavelength-shiftingaptamer, wherein upon binding a (fluorescence) wavelength-shiftingaptamer switches fluorescence wavelength from one wavelength to anotherwavelength. Thus, a (fluorescence) wavelength-shifting aptamer canreduce background signals in a human body's blood/biological fluid.

A molecular beacon is looped like a hairpin. The loop-like hairpin cancontain a molecular probe sequence, which is complementary to a diseasespecific nucleic acid molecule. The molecular beacon can be chemicallycoupled with a fluorophore at one end and a non-fluorescent quencher atthe other end.

Furthermore, in addition to molecular quenchers, many nanomaterials(e.g., graphene oxide) also possess excellent quenching efficiency.

Upon binding to the disease specific nucleic acid molecule, themolecular probe sequence undergoes a spontaneous conformationalreorganization, which removes the fluorophore from the vicinity of thequencher and restores its fluorescence.

Optionally, the molecular beacon can be chemically coupled with two (2)or more fluorophores/quantum dot fluorophores,assembled/fabricated/constructed, utilizing the tip of an atomic forcemicroscope.

Furthermore, the molecular beacons chemically coupled with fluorophores(each fluorophore has a distinct fluorescence emission) can be utilizedas an array of disease specific biomarkers.

Similar to the molecular beacon, a synthetic/engineered riboswitchbeacon can be chemically coupled with a fluorophore at one end and anon-fluorescent quencher at the other end.

Furthermore, each synthetic/engineered riboswitch can be designed with asynthetically designed biological logic circuit wherein the output ofone synthetic or engineered riboswitch can activate/deactivate anotherdownstream synthetic or engineered riboswitch with a syntheticallydesigned biological logic circuit. This can enable one to answer whetherbiological fluid/blood contains a biomarker A and biomarker B, but not abiomarker C.

By Way of an Example and not by Way of any Limitation, MolecularThree-Dimensional Self-Assembly of Biomarker Binder

Utilizing a molecular self-assembly process, a three-dimensionallyorganized (e.g., an array) biomarker binder (e.g., anantibody/aptamer/riboswitch) can be fabricated/constructed in a suitablepolymer matrix (e.g., poly(N-isopropylacrylamide)) to enable improvedsensitivity. The biomarker binder and polymer matrix can repel eachother, so that the biomarker binders can arrange themselves in astructure/configuration that minimizes chemical interactions betweenthem.

Array of Fluidic Containers Sudden/Abruptly Constricted Fluid ChannelsBased Optical Integrated Diagnostic Biomodule (Configured by an Array ofOptical Fibers, a N×1 Optical Switch & Multiplexing of BiomarkerBinders) for Detection of a Disease Specific Biomarker/an Array ofDisease Specific Biomarkers

A way to inject a large molecule, nanoshell 120, protein/viral proteinand RNA (from a micro reservoir/microelectro-mechanical-systemreservoir) into a cell/stem cell/T cell is by squeezing the cell/stemcell/T cell through a (planar) sudden/abruptly constricted fluidchannel. During such a passage through the (planar) sudden/abruptlyconstricted (about 25% to 75% smaller than the diameter of cell/stemcell/T cell) fluid channel at a high speed, a temporary tiny opening inthe cell/stem cell/T cell membrane is formed, without any permanentdamage to the cell/stem cell/T cell.

The above configuration can be utilized to (a) inject bioactivecompounds 100 and/or bioactive molecules 100A or (b) the nanoshell 120to synthesize protein on-demand (as discussed earlier) or (c) thenanoshell 120 to deliver the CRISPR-Cas9 or optogenetics CRISPR-Cas9system into cell/stem cell/T cell (as discussed earlier) to analyze theeffectiveness of the bioactive compounds 100 and/or the bioactivemolecules 100A and/or synthesized protein on-demand. An amino acid,DNA/modified DNA (wherein DNA/modified DNA encapsulated/caged in/with aphotolabile protecting group) and a ribosome can be encapsulated/cagedin the nanoshell 120. An incident light can activate the photolabileprotecting group to synthesize a desired protein on-demand in-vitro andin-vivo in the nanoshell 120.

The above configuration can be utilized to inject a viral protein intoimmune cells to analyze the effectiveness of the viral protein. Theabove configuration can be also utilized to inject a protein todifferentiate stem cells (into specialized tissues) to analyze theeffectiveness of the protein.

For injecting and/or analyzing an array of large molecules, nanoshells120, proteins/viral proteins and RNAs into a diversity of differentcells/stem cells, a cascaded configuration of an array of (planar)sudden/abruptly constricted fluid channels can be utilized.

For example, an array of fluid containers based integrated opticaldiagnostic biomodule 700.3/700.4 can be further integrated by an arrayof (planar) sudden/abruptly constricted fluid channels, wherein each(planar) sudden/abruptly constricted fluid channel in a horizontal planeis connected/coupled with each fluid container.

A fluid container or a zero-mode waveguide can be integrated by an arrayof (planar) sudden/abruptly constricted fluid channels.

Array of Liquid Core Ring Resonators Sudden/Abruptly Constricted FluidChannels Based Optical Integrated Diagnostic Biomodule for Detection ofa Disease Specific Biomarker/an Array of Disease Specific Biomarkers

Optionally a cascaded configuration (for injecting an array of largemolecules, nanoshells 120, proteins/viral proteins and RNAs one afteranother in a cascaded manner into a diversity of different cells/stemcells) of an array of (planar) sudden/abruptly highly constrictedfluidic channels can be integrated with an array of liquid core opticalring resonators.

Each liquid core optical ring resonator has a fluidic container, whosecircular cross section forms a ring resonator. A human body'sblood/biological fluid can be passed through the liquid core opticalring resonator capillary, while a waveguide arranged perpendicularly tothe fluidic container configured to deliver/couple light into a humanbody's blood/biological fluid core optical ring resonator wallevanescently via a presence of the evanescent field of the whisperinggallery mode.

The liquid core optical ring resonator and the whispering gallery modederive its sensitivity from monitoring frequency shift, induced bybinding (of a biomarker with a biomarker binder) at the sites of highlyconfined field intensities.

Furthermore, the field intensity can be amplified by excitation ofplasmon resonances in a nanoparticle layer/layer of an array ofplasmonic optical nanoantennas attached to a fluorophore.

By way of an example and not by way of any limitation, a plasmonicoptical nanoantenna can consist of two triangular pieces of gold, eachabout 75 nanometers long, whose tips face directly across from eachother in the shape of a miniature bowtie.

One method to increase the sensitivity is to implement a referencemeasurement in a proximate liquid core optical ring resonator capillary.

Another method to increase the sensitivity is by pushing more light formore light-matter interaction or by reducing the wall thickness and/orfabricating concentric rings.

In-Situ DNA Microarray Chip with Dual Array of Micromirrors to DetermineSuitability of Bioactive Compounds &/or Bioactive Molecules for Treatinga Disease/an Array of Diseases

As before, an array of miniature mirrors to pattern/deflect light via acombination of a shutter and a lens to the bottom of each fluidiccontainer (for example in FIG. 12A) from a single light source. Thisparticular configuration can enable the analysis of each fluidiccontainer at a time.

Furthermore, each fluidic container (for example in FIG. 12A) with aflat rectangular bottom can be coupled to an optical fiber (and DNAsynthesizer as well).

The array of micromirrors (as virtual masks) can reflect/focus thedesired pattern of light (e.g., ultraviolet light/nitrogen laser beamonto the flat rectangular bottom via a combination of a shutter andlens-including a metamaterial negative refractive index opticalsuperlens) with individually addressable mirrors controlled by acomputer. Each micromirror is individually controlled and it can rock onits angle about 2 milliseconds time scale.

A metamaterial negative refractive index optical superlens can befabricated/constructed, utilizing nanoscale patterns (e.g., photoniccrystals).

However, a metamaterial negative refractive index optical superlens forultraviolet light can be fabricated/constructed, utilizing alternatingnanometer-thick layers of silver (Ag) and titanium dioxide (TiO₂)—Thistype of design has a stack of strongly coupled waveguides sustainingbackward waves, the metamaterial exhibits a negative index of refractionto incoming light, regardless of its angle of propagation.

Furthermore, the computer also controls the delivery of chemicals. Thelight can cleave a photo-labile protecting group at the precise locationwherein the next nucleotide is to be coupled. The desired pattern oflight can be coordinated with the DNA synthesizer, such that there are385,000 to 4.2 million unique probes on a DNA microarray chip.

Such a DNA microarray chip in fluidic container can enable a suitabilitymeasurement of bioactive compounds 100 and/or bioactive molecules 100Ain treating a disease.

Electrical Diagnostic Biomodule for Detection of a Disease SpecificBiomarker/an Array of Disease Specific Biomarkers

Graphene is a two-dimensional crystal with a high carrier mobility andlow noise. It has the ideal properties to be an excellent component ofelectrical circuits. Graphene epitaxially grown on silicon carbide (SiC)substrate can be suitable for production of electrical circuits.

Graphane is a graphene variant, wherein hydrogen atoms are attached tothe carbon lattice in insulating layers.

Graphyne is a one-atom-thick sheet of carbon that resembles graphene,except that its two-dimensional framework (of atomic bonds) containstriple bonds in addition to double bonds.

Graphyne has a graphene-like electronic structure resulting ineffectively massless electrons due to Dirac Cones. All electrons aretravelling at roughly the same speed (about 0.3 percent of the speed oflight). This uniformity leads to conductivity greater than copper.

Graphyne can be utilized as a semiconductor practically as-is, ratherthan requiring noncarbon dopant atoms to be added as a source ofelectrons, as noncarbon dopants are required for graphene. Furthermore,structures of graphyne crystals allow electrons to flow in onedirection.

Molybdenite (MoS₂) is also a two-dimensional crystal with a naturalbandgap. It can be suitable for production of electrical circuits.

FIG. 13A illustrates an electrical diagnostic biomodule 840A based onchanges in electrical characteristics of a two-dimensional crystal basedfield effect transistor (e.g., graphene or molybdenite) due to a diseasespecific biomarker 460 (in a patient's biological fluid 440) which canbe propagated through a fluidic channel 620 to a fluidic cavity 520).

The disease specific biomarker 460 can chemically bind with a diseasespecific biomarker binder 240C on the optional biomolecular interfacelayer 480 on a single layer of the two-dimensional crystal substrate820.

The field effect transistor can integrate: a semiconductor substrate asa gate 720, a gate oxide insulator thin-film 740, a source metalthin-film 760, a drain metal thin-film 780, a polymeric insulatorthin-film 800 and a two-dimensional crystal substrate 820.

Furthermore, graphene's ability to form chemical bonds can be turned onor turned off based on what is underneath the graphene. When silicondioxide is underneath graphene, it is reactive when exposed to certainbiomarkers/chemicals. But when boron nitride is underneath graphene, itis not reactive when exposed to certain biomarkers/chemicals. An arrayof materials (e.g., an array of boron nitride and silicon dioxide)underneath graphene can be utilized with an array of sensors to detect atrace amount of biomarkers/chemicals.

Microelectro-Mechanical-System Biomodule to Draw/Propagate Blood

FIG. 13B illustrates a microelectro-mechanical-system biomodule 700B todraw blood from a patient, utilizing the microneedle 340, which can bemonolithically integrated with a micromachined (voltage deflectable)membrane 660, a membrane sensor 680 and a fluidic channel 620.

A microneedle 340 can be electrically powered and programmed to draw thepatient's blood at a periodic interval of time.

Furthermore, the microelectro-mechanical-system biomodule 700B caninclude an array of microneedles 340, an array of micromachinedmembranes 660, an array of membrane sensors 680 and an array of fluidicchannels 620.

Furthermore, an array of fluidic channels 620 can be placed onto anarray of precise silicon/ceramic v-grooves 640.

The array of precise silicon/ceramic v-grooves 640 can be enclosedwithin a precisely machined connector (not shown in the FIG. 13B).

The precisely machined connector can be attached precisely/detached fromthe microelectro-mechanical-system biomodule for drawing/propagating thepatient's blood.

An Integrated Two-Dimensional Crystal Field-Effect Transistor BasedElectrical Diagnostic Biomodule for Detection of a Disease SpecificBiomarker/an Array of Disease Specific Biomarkers

FIG. 13C illustrates an integrated two-dimensional crystal field-effecttransistor based electrical diagnostic biomodule 840.

Engineered Protein Based Field-Effect Transistor to ReplaceTwo-Dimensional Crystal Field-Effect Transistor

Furthermore, the two-dimensional crystal field-effect transistor can bereplaced by an engineered protein based field-effect transistor. Theengineered protein based field-effect transistor can befabricated/constructed, utilizing a suitable material decorated onengineered protein (e.g., a three-dimensional ball and spike engineeredprotein-synthesized by a fusion of both Dps and gp5c genes).

Proton Based Field-Effect Transistor Decorated with a Lipid Layer toReplace Two-Dimensional Crystal Field-Effect Transistor

FIG. 13D illustrates a proton field-effect transistor and itincorporates a semiconductor substrate as a gate 720, a gate oxideinsulator thin-film 740, a source metal thin-film 760, a drain metalthin-film 780 for proton current and a nanowire 820E.

Palladium hydride contacts can replace the source metal or drain metal.The chitosan/melanin based nanowire 820E (connecting the source metalthin-film 760 and the drain metal thin-film 780) can be decorated with alipid layer (a double wall of oil molecules, that biological cellsutilizes to separate its inside from its outside environment) 820G. Thelipid layer 820G can be decorated with a disease specific biomarkerbinder 240C.

The disease specific biomarker binder 240C can chemically bind with adisease specific biomarker 460—thus it can change the electricalcharacteristics of the proton field-effect transistor 820E.

Furthermore, the proton field-effect transistor can be integrated with ananotube (e.g., a boron nitride/carbon/tubular structure nanotube,fabricated/constructed by DNA/RNA origami process) 120G based nanoradiotransmitter with a nanoantenna 900A.

The nanotube 120G based nanoradio transmitter with the nanoantenna 900Acan be electrically powered by a nanobattery 400A.

A miniaturized non-rechargeable lithium battery can replace thenanobattery 400A.

Glucose fuel cells (fabricated/constructed on a silicon substrate withintegrated platinum catalyst to strip electrons from glucose) canreplace the nanobattery 400A.

M13 bacteriophage can translate mechanical energy into electricalenergy. To improve the piezoelectric property of M13 bacteriophage, theouter protein layer of M13 bacteriophage can be engineered by addingappropriate molecules. Furthermore, to amplify the piezoelectric effect,multi-layers of engineered M13 bacteriophage can be utilized.Multi-layers of engineered M13 bacteriophage can then be sandwichedbetween two biocompatible electrodes to act as a battery, when stressedmechanically (e.g., by a cardiac cycle).

Similarly, prestin protein can convert tiny vibrations into a voltageoutput. Each prestin protein is only capable of making nanowatts ofelectricity. Many prestin proteins can be sandwiched between twobiocompatible electrodes to act as a battery, when stressed mechanically(e.g., by a cardiac cycle).

Furthermore, in melanin based electrical circuits both electron andproton can be utilized. A chitosan/melanin based proton field-effecttransistor integrated with the nanoradio transmitter with a nanoantenna900A and the nanobattery 400A can be indicated as 840C.

Silicon Nanowire Based Field-Effect Transistor Decorated with a LipidLayer to Replace Two-Dimensional Crystal Field-Effect Transistor

FIG. 13E illustrates a similar configuration as 13D except that asilicon nanowire replaces the chitosan/melanin nanowire.

A silicon nanowire field-effect transistor 820F integrated with thenanotube 120G based nanoradio transmitter, the nanoantenna 900A and thenanobattery 400A can be indicated as 840D.

Furthermore, the silicon substrate of silicon nanowire field-effecttransistor 820F can also be replaced by just melanin or a conductingpolymer.

A nanoantenna printed on a biocompatible material (e.g., silk) can beplaced in (within) a human body such that any change in current flow inthe nanoantenna can induce a change in the radio transmitter placed on ahuman body.

Furthermore, device configurations, as illustrated in FIG. 13D or 13Ecan be integrated with an organic semiconductor circuit. A shape memorypolymer can be laminated and cured on the organic semiconductor circuitor on the device, as illustrated in FIG. 13D or 13E.

Interface Electrode

Boron-doped conducting diamond-like material can be grown on a silicondioxide substrate by a chemical vapor deposition process at about 900degrees' centigrade.

Boron-doped conducting diamond-like material can be bonded on a polymersubstrate and then lifted off from the silicon dioxide substrate byhydrofluoric acid.

Thus, a boron-doped conducting diamond-like material can act as aninterface electrode for any biological application.

It should be noted an implantable (within a human body) miniaturediagnostic biomodules 840C and 840D can be rendered nonfunctional due tobiofouling, because of a triggered immune response.

A thermoresponsive material can contract and expand in response tochanges in temperature. Thus, the implantable (within a human body)miniature diagnostic biomodule can be coated with a biocompatiblethermoresponsive material (e.g., hydrogel). By increasing thetemperature of the biocompatible thermoresponsive material, thethermoresponsive material contracts, as proteins and cells are dislodgedfrom the coated surface of the thermoresponsive material. When the heatis removed, the thermoresponsive material can return to its normalstate. This heating/cooling process can be repeated until theimplantable (within a human body) miniature diagnostic biomodule iscleaned from biofouling.

Detection of a Disease Specific Biomarker/an Array of Disease SpecificBiomarkers & Programmable/Active Delivery of BioactiveCompounds/Bioactive Molecules in Near Real-Time/Real-Time

If 840C/840D detects an abnormal level of a disease specific biomarker460, then the nanoradio transmitter with the nanoantenna 900A cantransmit the information so that a microelectro-mechanical-systemreservoir can enable a programmable/active delivery of the bioactivecompounds 100 and/or bioactive molecules 100A in nearreal-time/real-time via a dynamic closed feedback loop.

Furthermore, an array of 840C/840D can be utilized instead of a single840C/840D.

Nanostructure Based Diagnostic Biomodule for Label-Free Detection of aDisease Specific DNA/Protein or an Array of Disease SpecificDNAs/Proteins

A probe DNA can be attached to a lipid layer on a nanostructure (e.g.,carbon nanotube/boron nanotube), utilizing an electrochemicalfunctionalization. The lipid layer can be replaced by a suitable polymerlayer. Alternatively, the nanostructure can be decorated by alipid-functional-spacer construct, which is commercially available fromKode Biotech.

In particular, the nanostructure can be decorated by alipid-functional-spacer construct at a single point defect (e.g.,fabricated/constructed by electrochemical oxidation/electrochemicaletching/atomic force microscopy based nanolithography) of thenanostructure. Alternatively, the nanostructure can be decorated by anaptamer, utilizing the DNA origami fabrication process at a single pointdefect of the nanostructure. The detection can be based on a uniqueimpedance measurement technique coupled to a field effect transistordevice, when a complementary target DNA binds with a probe DNA or aprobe DNA at the single point defect. Alternatively, a probe DNA can bereplaced by a disease specific designer protein. A disease specificdesigner protein has a leave-one-out configuration, wherein each proteinhas an omitted segment to create a binding site to fit a protein for aspecific disease.

In addition to a unique impedance measurement technique coupled to afield effect transistor device by electrical method, the nanostructurecan naturally fluoresce in its native state (e.g., prior to acomplementary target DNA binding with a probe DNA), when excited bylight (e.g., light from a laser or a light source, utilizing atwo-dimensional material (e.g., graphene) as described in FIG. 12Z1),but fluorescence emission from the nanostructure will change from itsnon-native state (e.g., upon binding complementary target DNA with aprobe DNA). This change in fluorescence emission can be utilized fordetection of disease specific DNAs and/or proteins and this change influorescence emission can be enhanced by integration of one or morethree-dimensional protruded structures and/or photonic crystals.

Furthermore, a particular two-dimensional material-graphene's ability toform chemical bonds can be turned on or tuned off based on what isunderneath the graphene. When silicon dioxide is underneath graphene, itis reactive when exposed to certain biomarkers/chemicals. But when boronnitride is underneath graphene, it is not reactive when exposed tocertain biomarkers/chemicals. An array of materials (e.g., an array ofboron nitride and silicon dioxide) underneath graphene can be utilizedby an array of sensors to detect a trace amount of biomarkers/chemicals.

Furthermore, an array of nanostructures can be utilized instead of asingle nanostructure for label-free detection of an array of diseasespecific DNAs and/or proteins by an electrical and/or optical method.The nanostructures (on a distinct semiconductor substrate (e.g.,silicon) for electrical method and on another distinct substrate (e.g.,quartz) for optical method) can be integrated with a complementarymetal-oxide semiconductor integrated circuit and/or a microfluidicdevice/nanofluidic device/flow cell. However, it should be noted that atransparent semiconductor substrate can minimize the need for twodistinct substrates. Such an array of nanostructures can enable thedetection of bacterial infection via quorum sensing (which allowsbacteria to communicate with each other to coordinate their geneexpression), disease specific biomarkers, engineered cells'/stem cells'expression of therapeutic proteins (e.g., as obtained through a (planar)sudden/abruptly constricted fluid channel in cell/stem cell/T cell),neural functions and viral infection.

Nanohole Based Diagnostic Biomodule for Detection of a Disease SpecificBiomarker/an Array of Disease Specific Biomarkers

Four (4) molecules, when chemically bonded together that make up thestructural units of DNA are: adenine (A), cytosine (C), guanine (G) andthymine (T). A segment of a DNA strand can be a gene.

Four (4) molecules, when chemically bonded together that make up thestructural units of RNA are: adenine (A), cytosine (C), guanine (G) anduracil (U).

FIG. 14A illustrates a nanotunnel 500C. The nanotunnel 500C can befabricated/constructed, utilizing a low-temperature atomic layerdeposition process on an atomically thick substrate.

Multi-layers of dielectrics 740B and metals 760B are embedded in thenanotunnel 500C.

A nanohole 500D is about 1.5 nanometers in diameter. The nanohole 500Dcan be fabricated/constructed just below the nanotunnel 500C.

Through an amazing coincidence, the graphene layer's thickness is about3.35A° or 0.335 nanometers, which exactly fits the gap between twoDNA/RNA molecules. Hence, the nanohole 500D can befabricated/constructed from atomically thick graphene.

Alternatively, the nanohole 500D can also be fabricated/constructed,utilizing two-dimensional material like molybdenum disulfide.

Alternatively, the nanohole 500D can also be fabricated/constructed,utilizing a tunable self-assembly material Ni₃(HITP)₂, which is acombination of nickel and an organic compound: HITP(2,3,6,7,10,11-hexaiminotriphenylene). Ni₃(HITP)₂ has graphene'sperfectly hexagonal honeycomb crystal structure. Furthermore, multiplethin-layers of Ni₃(HITP)₂ naturally form perfectly aligned stacks, withthe openings at the centers of the hexagons of about 2 nanometers.Since, Ni₃(HITP)₂ has a natural bandgap, electronic circuits can also befabricated/constructed.

Alternatively, the nanohole 500D can also be fabricated/constructed,utilizing the DNA/RNA origami process on the same atomically thicksubstrate. The DNA/RNA origami structure can be fabricated/constructedinto an accurately controlled size/shape of the nanohole 500D.

The nanohole 500D has four (4) embedded tunneling metal electrodes 820A.The four (4) embedded tunneling electrodes 820A are metal (e.g., goldnanoparticle based) tunneling electrodes. The four (4) embeddedtunneling metal electrodes 820A can be fabricated/constructed, utilizingthe DNA/RNA origami process.

Optionally, the tips of the tunneling metal electrodes 820A can haveultrasharp apexes with radii of curvatures of less than 1 nanometer.Electromagnetic fields are enhanced at the tip of the ultrasharptunneling metal electrodes 820, when they are irradiated with laserlight. Electromagnetic field enhancement can lead to an amplification ofsignals to enable even single molecule detection. The ultrasharptunneling metal electrodes 820 can enable field enhancement of 10¹¹ andlateral resolution less than 0.2 nanometers to identify/distinguish asingle molecule of the single stranded DNA/RNA 820D by laser inducedRaman spectroscopy. The ultrasharp tunneling metal electrodes 820 can becoated with a monolayer of diamond thin-film for contamination-freeoperation, stability and reliability.

The DNA origami process is a template for the design and fabrication ofnano-scaled structures. One can engineer selected staple strands on aDNA origami structure with site-specific attachment of goldnanoparticles to fabricate conducting nanowires from the DNA origaminanostructure.

Similarly, the RNA origami template can replace the DNA origamitemplate.

By way of an example and not by way of any limitation, the DNA/RNAorigami structure with site-specific attachment of gold nanoparticlescan act as a tunneling metal electrode.

Furthermore, polythiophene, a light emitting diode (LED) polymermolecule can be chemically bonded/attached/integrated with the tunnelingmetal electrode or chemically bonded/attached/integrated with the tip ofthe tunneling metal electrode.

FIG. 14B illustrates a set of two (2) embedded tunneling metalelectrodes 820A diametrically positioned as opposite to each other.

FIG. 14B also illustrates another set of two (2) embedded tunnelingmetal electrodes 820A diametrically positioned as opposite to eachother.

The nanohole 500D can be mechanically supported on a larger (about 2nanometers in diameter) nanohole in an atomically thick dielectric 740C.

The dielectric 740C can be fabricated/constructed, utilizing alow-temperature atomic layer deposition process.

The larger (about 2 nanometers in diameter) nanohole in the dielectric740C can be fabricated/constructed, utilizing electron beam lithographyand focused ion beam etching.

Furthermore, the larger nanohole (about 2 nanometers in diameter) in thedielectric 740C can be mechanically supported on fabricated/constructedon an atomically thick two-dimensional crystal (e.g., graphene,molybdenum sulfide and phosphorene) membrane 820.

The nanohole 740C can be mechanically supported by two (2) atomicallythick two-dimensional crystals (e.g., a combination of graphene andphosphorene, or a combination of molybdenum sulfide and phosphorene, ora combination of graphene and molybdenum sulfide).

Alternatively, the nanohole 740C can be fabricated/constructed directlyonto the atomically thick two-dimensional crystal membrane 820, whichcan be further supported by another atomically thick two-dimensionalcrystal membrane.

It should be noted that molybdenum sulfide is different from othersemiconductor materials, because it can be grown in layers of one atomthickness, without compromising its properties. In sharp contrast tographene, which is a semi-metal with no bandgap by nature, molybdenumsulfide monolayers offer an attractive semiconductor option due to adirect bandgap of 1.8 eV. Molybdenum sulfide monolayers are a bettercandidate than graphene for many electronic and photonic devices. Thus,a molybdenum sulfide monolayer deposited on a suitable substrate can beutilized for (a) an electronics circuit (e.g., an electronics circuit tomeasure transverse tunneling currents preciously), (b) tunnelingelectrodes and (c) a nanohole (fabricated/constructed, utilizingelectron beam lithography and focused ion beam etching) for identifyingmolecules in a single stranded DNA/RNA 820D, wherein the substrate inthe nanohole area is removed/etched back—further simplifyingfabrication/construction of a nanohole based diagnostic biomodule fordetection of a disease specific biomarker (e.g., a gene mutation)/anarray of disease specific biomarkers.

Unlike graphene, phosphorene is a natural semiconductor. Thus, aphosphorene monolayer deposited on a suitable substrate can be utilizedfor (a) an electronics circuit (e.g., an electronics circuit to measuretransverse tunneling currents preciously), (b) tunneling electrodes and(c) a nanohole (fabricated/constructed, utilizing electron beamlithography and focused ion beam etching) for identifying molecules in asingle stranded DNA/RNA 820D, wherein the substrate in the nanohole areais removed/etched back—further simplifying fabrication/construction of ananohole based diagnostic biomodule for detection of a disease specificbiomarker (e.g., a gene mutation)/an array of disease specificbiomarkers.

Furthermore, the nanohole in the atomically thick two-dimensionalcrystal membrane 820 is about 2 nanometers in diameter, which can beoptionally integrated with tunnel junctions.

Furthermore, the nanohole in the atomically thick two-dimensionalcrystal membrane 820 is about 2 nanometers in diameter, which can beoptionally integrated with a nanotransistor(s), as described in FIG.13C, FIG. 13D and FIG. 13E, built on top of the atomically thicktwo-dimensional crystal membrane 820.

Furthermore, the nanohole in the atomically thick two-dimensionalcrystal membrane 820 is about 2 nanometers in diameter, which can beoptionally integrated with a nanotransistor(s) such as graphenenanoribbon transistor, built on top of the atomically thicktwo-dimensional crystal membrane 820.

The atomically thick two-dimensional crystal membrane 820 can be ametallic graphene nanoribbon with zigzag edges or metallic chiralgraphene nanoribbon or wires made of a two-dimensional topologicalinsulator.

The nanohole 500D can be electrically connected to the atomically thicktwo-dimensional crystal membrane 820 for reliable electrical contact.

Alternatively, the nanohole 500D can be electrically connected to anatomically thick (about 1 nanometer thick) porous carbonnanomembrane/silicon nitride nanomembrane for reliable electricalcontact instead of the atomically thick two-dimensional crystal membrane820.

A single stranded DNA/RNA 820D can be pulled down through the nanotunnel500C and nanohole 500D by a vertical electrical field, as the DNA/RNA820D is electrically charged.

A four-point-probe measurement of transverse tunneling currents (ofabout 3A° long single molecule of the single stranded DNA/RNA 820D)through the nanotunnel 500C and nanohole 500D can electrically identifyeach single molecule of the single stranded DNA/RNA 820D.

Tunneling is confined to tiny distances such that a tunnel junction canidentify about 3A° long single molecule (e.g., adenine (A), cytosine(C), guanine (G) and thymine (T) of the single stranded DNA) of thesingle stranded DNA/RNA 820D at a time without interference from othermolecules.

Because of extreme sensitivity requirements in the measurement oftransverse tunneling currents, tiny vibrations can severely degrade atunneling signal.

A tiny voltage bias between the tunneling metal electrodes can enablepolythiophene, a light emitting diode (LED) polymer molecule to emitlight (e.g., light of red wavelength), which can be detected by anano-scaled detector (e.g., a detector based on graphene/molybdenumsulfide heterostructure or a detector based on nano-scaledthree-dimensional structure or a nanogap detector based on colloidalquantum dot).

Variations in optical intensity detection can also identify theapproximately 3A° long single molecule (e.g., adenine (A), cytosine (C),guanine (G) and thymine (T) of the single stranded DNA) of the singlestranded DNA/RNA 820D at a time without interference from othermolecules.

Additionally, current (surrounding the nanohole 560D) through theatomically thick two-dimensional crystal membrane 820 can be alsomeasured, as a single stranded DNA/RNA 820D can be pulled down throughthe nanotunnel 500C and nanohole 500D by a vertical electrical field, asa DNA/RNA 820D is electrically charged.

A large electric field is needed to push the single stranded DNA/RNA820D through the nanohole 500D, but the same large electric field canalso push single stranded DNA/RNA 820D too rapidly through the nanohole500D—thus reducing the ability of four embedded tunneling metalelectrodes 820A′ to sense/read individual molecules in single strandedDNA/RNA, utilizing the four-point-probe measurement of transversetunneling currents.

However, the pulling speed of the single stranded DNA/RNA 820D can bereduced by traversing the single stranded DNA/RNA 820D through analternating electric field generated by multi-layers of dielectrics 740Band metals 760B, embedding/surrounding the nanotunnel 500C.

The single stranded DNA/RNA can be chemically coupled to a magneticnanoparticle to push the single stranded DNA/RNA by a magnetic field inthe opposite upward direction with respect to the downward electricfield.

Furthermore, the pulling speed of the single stranded DNA/RNA 820D canbe reduced by chemically coupling phi29 DNA polymerase enzyme with thesingle stranded DNA/RNA or to the magnetic nanoparticle.

The tug-of-war between the electric field and the magnetic field(oppositely orientated with respect to each other) can be optimized toreduce the velocity of the single stranded DNA/RNA—thus allowing fourembedded tunneling metal electrodes 820A′ the ability to sense/readindividual molecules in the single stranded DNA/RNA, utilizing thefour-point-probe measurement of transverse tunneling currents.

Furthermore, a piezoelectric thin-film (e.g., zinc oxide or galliumnitride thin-film) can be deposited intimately surrounding the nanohole500D. The piezoelectric thin-film can be deposited by the atomic layerdeposition process. The piezoelectric thin-film physically can strain inresponse to an electric field—thus adjusting approximately the diameterof the nanohole 500D in-situ for reducing the velocity of the singlestranded DNA/RNA 820D.

A molecule can either be right-handed (D) or left-handed (L). Thisproperty is called chirality. A chiral molecule can recognize/transferinformation that has the same chirality (same handedness, L to L or D toD) and discriminate the molecule of different chirality (L to D and D toL).

The diametrically opposite first set of two (2) embedded tunnelingelectrodes 820A, wherein each embedded tunneling electrode is chemicallyconfigured with a recognition molecule 820B such that, the recognitionmolecule 820B for adenine (A) can effectively clutch adenine (A) of thesingle stranded DNA/RNA 820D.

The diametrically opposite second set of two (2) embedded tunnelingelectrodes 820A, wherein each embedded tunneling electrode is chemicallyconfigured with a recognition molecule 820C such that, the recognitionmolecule 820C for guanine (G) can effectively clutch guanine (G) of thesingle stranded DNA/RNA 820D.

Furthermore, an additional change in edge conduction current can bemeasured when the single stranded DNA/RNA 820D is pushed through thenanohole in the atomically thick two-dimensional crystal membrane 820.

The atomically thick two-dimensional crystal membrane 820 can be ametallic graphene nanoribbon with zigzag edges (ZGNR) or metallic chiralgraphene nanoribbon or wires made of a two-dimensional topologicalinsulator.

Nanohole Integrated with a Suitable Functional/Fluorescent Molecule & aNanoantenna for Single Molecule Fluorescence/Single Molecule RamanSpectroscopy

Furthermore, the single stranded DNA/RNA 820D can be also configured (ata sub-nanometer precision by dip pen lithography) with suitablefunctional/fluorescent molecules—thus improving the sensitivity andreliability of the molecular identification of the single strandedDNA/RNA 820D.

The nanohole 500D can be integrated (utilizing dip pen lithography) witha suitable functional fluorescent molecule.

Furthermore, the proximity or vicinity of the nanohole 500D can beintegrated with a plasmonic optical nanoantenna, for single moleculefluorescence or single molecule Raman spectroscopy, when the singlestranded DNA/RNA 820D is also appropriately decorated with suitablefunctional molecules.

By way of an example and not by way of any limitation, a plasmonicoptical nanoantenna can consist of two triangular pieces of gold, eachabout 75 nanometers long, whose tips face directly across from eachother in the shape of a miniature bowtie.

Furthermore, the plasmonic optical nanoantenna can be integrated with alens based on metamaterial.

It may not be necessary to uniquely identify all four (4) molecules forsome applications. A binary conversion of molecular sequence (e.g., A orT=0, and G or C/U=1) can be utilized to identify a disease specificbiomarker and/disease specific genomic alteration/elimination in thesingle stranded DNA/RNA 820D.

Furthermore, statistics enhanced repeated four-point-probe measurementsof transverse tunneling currents can reliably identify each singlemolecule of the single stranded DNA/RNA 820D—thus detecting analteration/elimination of a single molecule in the single strandedDNA/RNA 820D, without need of PCR and Sanger sequencing.

Furthermore, such a two-dimensional array of the nanotunnels 500C andthe nanoholes 500D can sequence many single stranded DNA/RNA 820D inparallel.

Sequencing of DNA/RNA can generate Big Data.

Analysis of Big Data Related to Biology

Big Data can be converted into a smaller data set, utilizing linearsimplification and/or signal clustering, as the underlying data hasgeometrical structures and patterns (repeated over time). Furthermore,signal clustering can be categorized and weighted for importance.Alternatively, topological data analysis or Bayesian analysis coupledwith Markov chain Monte Carlo methods can be utilized for analysis ofBig Data. Analysis of Big Data can be coupled with an augmentedintelligence modeling algorithm and/or predictive modeling for adisease/an array of diseases. Furthermore, analysis of Big Data in anunstructured format can also be realized by a cloud based machinelearning/deep learning neural networks based learning/relearninginteractive expert cognitive computer, utilizing a natural language.Furthermore, analysis of Big Data can be coupled with an intelligentlearning set of instructions. An intelligent learning set ofinstructions can include: artificial intelligence (includingself-learning artificial intelligence), computer vision (includingself-learning computer vision), data mining, fuzzy/neuro-fuzzy logic,machine vision (including self-learning machine vision), naturallanguage processing, neural networks (including self-learning neuralnetworks), pattern recognition, reasoning modeling and self-learning(including evidence based self-learning).

It should be noted that artificial intelligence (including self-learningartificial intelligence), computer vision (including self-learningcomputer vision), data mining, fuzzy/neuro-fuzzy logic, machine vision(including self-learning machine vision), natural language processing,neural networks (including self-learning neural networks), patternrecognition, reasoning modeling and self-learning (including evidencebased self-learning) can be enhanced by quantum computing or quantumcomputing based machine learning.

At the heart of a quantum computer is a quantum bit (qubit)—a basic unitof information analogous to a classical bit 0/1 represented by atransistor in a classical computer. The qubit is exponentially morepowerful than the classical bit 0/1, because of its two uniqueproperties: it can represent both 1 and 0 at the same time. But forqubit to be useful, it must achieve both quantum superposition (likebeing in two physical states simultaneously) and quantum entanglement(like what happens to one qubit can instantly affect the other qubit,even when they are physically separated) and these two unique propertiescan be easily upset by a slightest disturbance (e.g., a materialdefect/vibration/fluctuating electric fields/noise). Therefore, qubitsare extremely susceptible to error, without operating at an extremelylow temperature. A quantum computer enhanced machine learning algorithmis an approach that enables a quantum computer to learn/relearn and tomake predictions—by combining machining learning with quantumcomputation. A quantum computer enhanced machine learning algorithm canbe compiled on one or more microprocessors, or one or more neuralnetwork based microprocessors and downloaded onto the quantumcomputer-classical computer interface for execution.

Details of the intelligent learning set of instructions have beendescribed/disclosed in U.S. Non-Provisional patent application Ser. No.14/999,601 entitled “SYSTEM AND METHOD OF AMBIENT/PERVASIVEUSER/HEALTHCARE EXPERIENCE”, filed on Jun. 1, 2016 and the entirecontents of this US Non-Provisional Patent Application are incorporatedherein.

By utilizing biostatistics, data mining algorithms (e.g., a topologicaldata mining algorithm), genomics, proteomics, augmented intelligencemodeling algorithm and/or predictive modeling algorithm, a set ofprimary predictive genes/proteins for a specific disease may bedetermined.

The nanohole based diagnostic biomodule (including the two-dimensionalarray of the nanotunnels 500C and two-dimensional array of nanoholes500D) for detection of a disease specific biomarker/an array of diseasespecific biomarkers is identified as 840.1.

Furthermore, 840.1 is integrated with a suitable port to input/drop aDNA/RNA sample and 840.1 can connect to the USB port of a personalcomputer for displaying and analyzing the DNA/RNA sample. The ability tocorrelate a patient's DNA with a specific disease treatment can bebeneficial.

Nanohole Based Diagnostic Biomodule for Application to PersonalizedMedicine

Most treatments today rely on clinical data taken from average patients.However, the individual response to different drugs can vary remarkablyeven to the point where an effective dose tolerated by one individualcould be completely ineffective or even toxic to another.

In many cases, this can be due to the Cytochrome P450 (CYP450) family ofproteins which is responsible for the metabolism of most drugs intoactive forms and/or forms that can be excreted from the body. The CYP450family of proteins is not large, but different people can expressdifferent members of the family and/or express the same members atdifferent levels. Knowing this information is the first step towardsdelivering personalized medicine—thus drug doses can be tailored to theindividual. The sequencing of a human genome, identification of genefamilies (such as CYP450) and a greater understanding of the geneticsbehind responses to drugs may allow delivery of personalized medicine.

The nanohole based diagnostic biomodule 840.1 can rapidly and reliablyanalyze samples from a patient to determine the presence of specificgenetic sequences which predisposing them to disease or sensitivity tospecific bioactive compounds and/or bioactive molecules and/or drugs andalso the levels and types of proteins that they are producing (such asCYP450 family members).

The nanohole based diagnostic biomodule 840.1 can include a first deviceto isolate an exosome (wherein this first device can include a magneticbead and/or a nano-scaled filter to filter one or more exosomes) and asecond device to separate a molecular component(s) within the exsosome.Details of the first device and second device are described in laterparagraphs.

Nanohole Based Diagnostic Biomodule for Application to EpigeneticFactors

If genome/genes are the blueprint of life, the epigenome is life'sEtch-a-sketch. Our lives are little more than a checklist of variousgenes on a genetic scantron sheet that can be turned on or off. Theregulation of gene expression is controlled by multiple mechanisms, suchas the sequence-specific binding of transcription factors to DNA,epigenetic signals and a dynamic chromatin state. Epigenome isresponsible for the determination of the cell type and cell activity.Epigenetic regulation of genes acquired during early development isinherited not only during cell division (mitotic inheritance), but itcan be passed on from one generation to the next (meiotic inheritance),but how long these changes persist remains unclear. Epigenetic changes,like so many vital biological processes, fall to human bodies to dealwith. Genes become epigenetically set to deal with conditions (e.g.,diet, lifestyle and stress) and then pass that on to the nextgeneration. Epigenetics holds great promise in the area of personalizedmedicine. When human eats, his/her metabolism changes, but food doesn'tchange a cell's genome. Instead, food modulates the epigenome, themolecular markers on the chromatin that influence gene expression byaffecting how tightly DNA is wrapped around its protein scaffolding.

Epigenetic factors (guided by molecular architect piRNAs) traverse thestatic genome and turn the genes on or off. The staggering number ofpotential combinations of active and inactive genes explains why arelatively small number of genes can carry out such a wide range offunctions. If a cell has ever turned on a gene in the past, the piRNAwill recognize it and allow it to be expressed.

But if a gene has not been active in a cell before, the piRNA will setthe silencing mechanism into action so it remains off. The silencing orlack of silencing is permanent. If the piRNA doesn't silence a gene thefirst time it encounters it, it won't ever silence it. And if itsilences it once, then every time that gene appears in the future, thesystem will turn it off.

Several types of cancers can be triggered when the wrong kinds of piRNAsguide epigenetic factors to activate the wrong genes. Blocking theaction of these piRNAs should become a new opportunity to treat cancers.

Epigenetic mechanisms involve adding chemical tags to DNA or theproteins it is wrapped around. Changes to the cell's environment causethe chemical tags to be added or removed. These epigenetic markers arepassed on to daughter cells when the original cell divides in two.Mapping the epigenome—all the chemical modifications to the DNA and itsprotein scaffolding that are used to switch genes on and off throughoutan organism's life is critical and can be achieved by the nanohole baseddiagnostic biomodule 840.1.

Differences in the epigenetic markers carried on a genome may alsoexplain some of the differences between apparently identicalindividuals, due to diet, lifestyle and stress.

A connectivity brain scan (measures water diffusion in a human brain)can map the strength of neural connections and how information is routedin a human brain to estimate risk factors for neurological diseases(e.g., Alzheimer's disease). Furthermore, the above connectivity scancan be correlated with a gene sequencing to determine a genetic errorfor Alzheimer's disease.

Alternatively, FIG. 14C illustrates another DNA/RNA sequencing system840.2, wherein DNA/RNA can be pulled through a nanohole on an angstromthin membrane (the angstrom thin membrane is mechanically supported bysilicon nitride and/or silicon membrane). The angstrom thin membrane canbe fabricated/constructed in a two-dimensional material. In case of DNA,upon passing through the nanohole, a cutting enzyme (e.g., utilizingCRISPR-Cas9) can cut nucleotides A, C, G and T of DNA in a reactiontube. Then, each nucleotide (chemically coupled with a colloidalmolecule) passes through a specific reaction zone of the reaction tubeand then it is identified by an ultrasensetitive Ramanspectrophotometer.

Additionally, a Raman nanoprobe can be chemically coupled withnucleotides A, C, G and T of DNA to enhance the Raman signal. Forexample, a Raman nanoprobe can be a nanotube (e.g., a single-walledcarbon nanotube) encapsulating/caging dye molecules, can enhanceenhancement of the Raman signal, wherein the nanotube can suppressunwanted fluorescence signals. The nanotube can be 1 nanometer indiameter and 300 nanometers in length, encapsulating/caging about 500 to1000 dye molecules.

Additionally, at the zone of Raman measurement, an opticalnanoantenna(s) can be fabricated/constructed to enhance the Ramansignal. The optical nanoantenna(s) can be also embedded with a supportedphospholipid membrane (phospholipid membrane is fluid at roomtemperature). This can enable mobile nucleotides (e.g., adenine (A),cytosine (C), guanine (G) and thymine (T)) within the bilayer membraneto enter the hot-spot region(s) of the optical nanoantenna(s) viadiffusion and can therefore be measured by an ultrasensetitive Ramanspectrophotometer.

The DNA/RNA sequencing system 840.2 can be utilized also for exomesequencing. In case of RNA, RNA-targeted Cas9 (RCas9) with CRISPR can beutilized to cut RNA molecule.

The optical biomodule in FIG. 14C can include a first device to isolatean exosome (wherein this first device can include a magnetic bead and/ora nano-scaled filter to filter one or more exosomes) and a second deviceto separate a molecular component(s) within the exsosome. Details of thefirst device and second device are described in later paragraphs.Bioinformatic analysis of molecular components within exosomes cangenerate a large set of Data—Big Data. The analysis of Big data isdescribed in previous paragraphs.

FIGS. 14D-14G illustrate chemically coupling to cut nucleotides A, C, Gand T of the DNA with a colloidal molecule respectively.

FIG. 14H illustrate the Raman shift spectrum of nucleotides A, C, G andT of the DNA respectively.

FIGS. 14I-14J illustrate another nanohole based single molecule DNA/RNAsequencing optical diagnostic biomodule 840.3. FIG. 14I illustrates anoptical system for excitation by laser and detection of light. FIG. 14Jillustrates another DNA/RNA sequencing system 840.3, wherein DNA/RNA canbe pulled through a nanohole on an angstrom thin membrane (the angstromthin membrane is mechanically supported by silicon nitride and/orsilicon membrane). The angstrom thin membrane can befabricated/constructed in a two-dimensional material. In case of DNA,DNA passing through the nanohole, nucleotides A, C, G and T of DNA areexcited in a time sequence (e.g., 0 millisecond, 45 milliseconds, 90milliseconds, 180 milliseconds and 360 milliseconds) by the opticalsystem and the respective optical signal is measured by a detector (asillustrated in FIG. 14I). The DNA/RNA sequencing system 840.3 can beutilized also for exome sequencing.

FIG. 14K illustrates a microfluidic waveguide configuration to separate(blood) plasma from blood via an inlet/outlet.

FIG. 14L illustrates another microfluidic waveguide configuration toseparate (blood) plasma from blood via an inlet/outlet.

FIG. 14M illustrates a portable diagnostic device, which can be coupledwith a machine learning/deep learning neural networks based (withlearning/relearning configuration) healthcare application (“app”) on theportable internet appliance 1600.

FIG. 14N illustrates an example of a machine learning/deep learningneural networks based (with learning/relearning configuration)healthcare application on the portable internet appliance 1600.

Furthermore, the machine learning/deep learning neural networks based(learning/relearning) healthcare application on the portable internetappliance 1600 can be wirelessly connected to a cloud based expertsystem, which has the significant computing power of a supercomputer ora quantum computer.

Plasmonic Microhole/Nanohole Based Diagnostic Biomodule for Detection ofa Disease Specific Biomarker/an Array of Disease Specific Biomarkers

Furthermore, the nanohole based diagnostic biomodule (including thetwo-dimensional array of the nanotunnels 500C and two-dimensional arrayof nanoholes 500D) for detection of a disease specific biomarker/anarray of disease specific biomarkers identified as 840.1 can beintegrated with a plasmonic microhole/nanohole based diagnosticbiomodule for validation.

A plasmonic microhole/nanohole based diagnostic biomodule can befabricated/constructed with an array of microholes/nanoholes on a metalfoil/metalized thin-film/metalized ultra thin-film, wherein the lightfrom the bottom of the metal foil/metalized thin-film/metalized ultrathin-film can set plasmons to work on the surface and wherein eachmicrohole/nanohole is coated with a different disease biomarker binder.Plasmons trap so much energy around each microhole/nanohole that theycan convert more light on the top of the metal foil/metalizedthin-film/metalized ultra thin-film. If a disease biomarker from a humanbody's blood/biological fluid binds with a respective disease biomarkerbinder, then it will attenuate the light intensity of an incident lightbeam (e.g., a laser beam).

Optionally, each microhole/nanohole can be decorated with a syntheticDNA strand designed to bind with a specific disease (e.g., a specificcancer) cell from a human body's blood/biological fluid. If the specificdisease cell from a human body's blood/biological fluid binds with therespective synthetic DNA strand, then it will attenuate the lightintensity. Furthermore, captured disease cells can be separated/squeezedinto a petri dish. Then various bioactive compounds 100 and/or bioactivemolecules 100A or drugs can be added to the separated/squeezed diseasecells to evaluate the most effective treatment for the specific disease.

Bioelectronics Subsystem for Detection of a Disease SpecificBiomarker/an Array of Disease Specific Biomarkers & Programmable/ActiveDelivery of Bioactive Compounds &/or Bioactive Molecules in NearReal-Time/Real-Time

FIG. 15A illustrates an integrated bioelectronics subsystem 960 fordetection of a disease specific biomarker/an array of disease specificbiomarkers and programmable/active delivery of bioactive compounds 100and/or bioactive molecules 100A in near real-time/real-time.

The integrated bioelectronics subsystem 960 at least can include (a) amicroelectro-mechanical-system biomodule 420/420.1, (b) an integratedoptical diagnostic biomodule 700.1/700.2/700.3/700.4, (c) an integratedelectrical diagnostic biomodule 840/840.1 and (d) an electronic module940.

Furthermore, the electronics module 940 can be fabricated/constructed ona flexible/bendable/stretchable substrate by lifting off the electronicscircuit layer from a rigid semiconductor substrate and thenbonding/connecting, the lifted off electronics circuit layer onnanoribbons of wires mounted onto a lightweight and stretchablemembrane, wherein the wires can bend, twist and stretch, whilemaintaining their functionality.

The integrated bioelectronics subsystem 960 can stick to the biologicaltransport medium (e.g., skin) via the van der Waals force, without theneed of an adhesive.

Thus, the integrated bioelectronics subsystem 960 can be removed easilyfrom the biological transport medium.

The electronics module 940 can integrate: (a) an electrical powerproviding component 400, (b) a microprocessor component 860, (c) amemory/data storage component 880, (d) a wireless (radio) transceivercomponent 900 and (e) an embedded operating system algorithm 920.

By way of an example and not by way of any limitation, the wireless(radio) transceiver component 900 can be configured with Wibree,Bluetooth, Wi-Fi and near-field communication.

Other bio/health sensors to monitor vital health parameters (e.g., bloodsugar and heart rate) can be integrated with the electronics module 940to monitor vital health parameters (e.g., blood sugar and heart rate).

Silicon-On-Insulator as an Integration Platform Substrate for theIntegrated Bioelectronics Subsystem 960

For fabricating/constructing a compact bioelectronics subsystem 960optical components/electronics circuitry components can be attached(including flip-chip bonding on metalized thermal bumps integrated withthin-film solder) on silicon-on-insulator as an integration platformsubstrate.

Printed Electronics Over a Three-Dimensional Structure forMiniaturization/Manufacturing of the Integrated Bioelectronics Subsystem960

An aerosol jet can atomize nanoparticle based print materials intomicroscopic droplets. These microscopic droplets can be focused,utilizing a sheath of gas into a precise jet stream by a nozzle.

The nozzle can be placed about 5 millimeters away from asurface/irregular shaped surface.

Both the nozzle and a container securing the surface/irregular shapedsurface can be manipulated through different angles to print (sizesmaller than 0.01 millimeters wide) on a three-dimensional structure.

Higher levels of miniaturization and manufacturing can be realized,utilizing printed electronics (e.g., aerosol nanoparticle jet to printan antenna, electronics circuitry, radio frequency component andsensor).

Furthermore, printed electronics can print a section of the integratedbioelectronics subsystem 960 over a three-dimensional structure, insteadof assembling many discrete components.

However, printed electronics can be extended to any substrate of anymaterial of any shape.

For example, resting arms of a wheel chair can be printed with variousbio/health sensors to monitor vital health parameters (e.g., bloodpressure, blood sugar, heart rate, % oxygen in blood and weight) andlow-power wireless sensors (e.g., Wibree, Bluetooth, Wi-Fi andnear-field communication) to transmit such vital health parameters to aportable internet appliance for statistical analysis, then eventually toa healthcare professional.

Alternatively, fiber-reinforced composite/thermoplastic composite can beutilized to reduce the weight of the wheel chair. Alternatively, ananocomposite material can include carbon nanotubes(single-walled/multi-walled) and/or graphene (or graphene likenanostructual material e.g., graphene flakes) and a poly vinyl alcohol(PVA) binder matrix, can be utilized to reduce the weight of the wheelchair. Carbon nanotubes (single-walled/multi-walled) and/or graphene (orgraphene like nanostructual material e.g., graphene flakes) can form aninterconnected network within the poly vinyl alcohol binder matrix. Incase of the combination of carbon nanotubes and graphene (or graphenelike nanostructual material e.g., graphene flakes), the strength of thenanocomposite material can be varied by changing the weight ratio (from0.1 to 1) of carbon nanotubes (single-walled/multi-walled) to graphene(or graphene like nanostructual material e.g., graphene flakes).Alternatively, a material matrix (of either carbon fiber orpolyacrilonitrile nanofiber) can be added with 1 wt % to 10 wt %graphene (or graphene like nanostructual material e.g., graphene flakes)and/or 1 wt % to 10 wt % nanotubes (e.g., boron nitride/carbon(single-walled/multi-walled)) to form a nanocomposite. Such ananocomposite can be utilized to reduce the weight of the wheel chair.

Furthermore, DuPont Kevlar with the addition of (1 wt % to 10 wt %)carbon fiber and/or (1 wt % to 20 wt %) carbon nanotubes(single-walled/multi-walled) and/or (1 wt % to 20 wt %) graphene (orgraphene like nanostructual material e.g., graphene flakes) can beutilized to reduce the weight (and increase strength) of the wheelchair/other tools. Alternatively, DuPont Kevlar with the addition of (1wt % to 10 wt %) carbon fiber and/or (1 wt % to 20 wt %) carbonnanotubes (single-walled/multi-walled) and/or (1 wt % to 20 wt %)graphene (or graphene like nanostructual material e.g., graphene flakes)and/or (1 wt % to 30 wt %) natural silk/synthetic silk can be utilizedto reduce the weight (and increase strength) of the wheel chair/othertools. Alternatively, DuPont HPF resins with the addition of (1 wt % to10 wt %) carbon fiber and/or (1 wt % to 20 wt %) carbon nanotubes(single-walled/multi-walled) and/or (1 wt % to 20 wt %) graphene (orgraphene like nanostructual material e.g., graphene flakes) can beutilized in fabricating/constructing other components/tools.Alternatively, DuPont HPF resins with the addition of (1 wt % to 10 wt%) carbon fiber and/or (1 wt % to 20 wt %) carbon nanotubes(single-walled/multi-walled) and/or (1 wt % to 20 wt %) graphene (orgraphene like nanostructual material e.g., graphene flakes) and/or (1 wt% to 30 wt %) natural silk/synthetic silk can be utilized infabricating/constructing other components/tools.

The integrated bioelectronics subsystem 960 can communicate with anintegrated intelligent expert algorithm. The integrated intelligentexpert algorithm can be located at a cloud based data storage unit or acloud based server, wherein the cloud based data storage unit or thecloud based server can be configured with additional hardware and/orsoftware to spill out volumes of wrong data, in the event of amemory-access-pattern security breach.

The integrated intelligent expert algorithm can include a first set ofintelligent learning instructions of artificial intelligence (includingself-learning artificial intelligence), computer vision (includingself-learning computer vision), data mining, fuzzy/neuro-fuzzy logic,machine vision (including self-learning machine vision), naturallanguage processing, neural networks (including self-learning neuralnetworks), pattern recognition, reasoning modeling and self-learning(including evidence based self-learning) for diseases/treatments.

It should be noted that artificial intelligence (including self-learningartificial intelligence), computer vision (including self-learningcomputer vision), data mining, fuzzy/neuro-fuzzy logic, machine vision(including self-learning machine vision), natural language processing,neural networks (including self-learning neural networks), patternrecognition, reasoning modeling and self-learning (including evidencebased self-learning) can be enhanced by quantum computing or quantumcomputing based machine learning.

The integrated intelligent expert algorithm can include a second set ofintelligent learning instructions of algorithm-as-a-service, patients'behavior/nutrition modeling, physical search algorithm and softwareagent

Furthermore, the integrated intelligent expert algorithm can include:statistical analysis (e.g., Student t-test, ANOVA (analysis of variance)and Chi-Square), data mining, ANN (artificial neural network),hierarchical cluster analysis, KNN (K-nearest neighbor analysis) andperformance analysis (e.g., specificity, sensitivity and accuracy).

Furthermore, the intelligent expert algorithm can be complemented by acollection of inputs (including identification of images) fromhealthcare professionals. The inputs from the healthcare professionalscan be in near real-time/real-time. These inputs can complement/enhancethe intelligent expert algorithm.

FIG. 15B illustrates a near real-time/real-time application of awearable integrated bioelectronics subsystem of 960.

The above bioelectronics subsystem 960 can enable nearreal-time/real-time measurement of a disease specific biomarker andinstantaneous programmable/active delivery of the bioactive compounds100 and/or bioactive molecules 100A in near real-time/real-time (via adynamic closed feedback loop).

The above bioelectronics subsystem 960 can enable nearreal-time/real-time measurement of a disease specific biomarker anddelayed programmable/active delivery of the bioactive compounds 100and/or bioactive molecules 100A in near real-time/real-time (via adynamic closed feedback loop), utilizing a remote wireless command froma healthcare professional.

Rapid Point-of-Care Detection of a Disease/an Array of Diseases by aDNAzyme/an Array of DNAzymes on a Substrate/Membrane with an Array ofPlasmonic Optical Nanoantennas

Gold nanoparticles absorb light. The wavelength of absorption depends onwhether the nanoparticles are separated or aggregated. The difference incolor can be seen with the naked eye. A powder of individual particlesappears red, but when the powder aggregates, it appears blue-violet incolor. The difference in color can be seen with a naked eye.

DNAzyme is a synthetic DNA molecule that can enzymatically split anothernucleic acid molecule.

Gold nanoparticles chemically bonded with DNAzyme in a powder/solutionform on a membrane/paper/polymer substrate. Furthermore, goldnanoparticles chemically bonded with DNAzyme may be preserved by dryingin sugar for an extended period of time.

When a disease specific gene from a human body's blood/biologicalfluid/syntheric biological circuit is introduced, the DNA can be cleavedfrom the gold nanoparticles, turning the color of themembrane/paper/polymer substrate red in color.

The membrane/paper/polymer substrate can have many strips. Each strip isconfigured with a disease specific DNAzyme to test a disease specificgene.

Furthermore, each separate strip of the membrane/paper/polymer substratecan be integrated with an array of large numbers (e.g., billions) ofplasmonic optical nanoantennas to significantly enhance the change incolor.

Rapid Point-of-Care Detection of a Disease/an Array of Diseases by aDesigner Protein/an Array of Designer Proteins on a Substrate/Membranewith an Array of Plasmonic Optical Nanoantennas

A membrane/paper/polymer substrate can have many strips/fluid cavities.Each strip/fluid cavity is configured with a disease specific designerprotein or a synthetic biomolecular circuit or a biomarker binder (e.g.,a DNAzyme) to test a specific disease.

A disease specific designer protein has a leave-one-out configuration,wherein each protein has an omitted segment to create a binding site tofit to a disease specific protein.

For example, a synthetic designed-in protein analogous to an abnormalprotein (produced by mutated BRCA1 gene or BRCA2 gene) has aleave-one-out configuration to create a binding site to detect thebreast cancer disease. The above example can be applied to an array ofsynthetic designed-in proteins analogous to abnormal proteins (producedby mutated BRCA1 gene or BRCA2 gene). Other mutations as singlenucleotide polymorphisms (SNP) in pieces of chromosomes may be linked toa higher breast cancer disease risk with an abnormal BRCA1 gene or BRCA2gene.

The disease specific design protein can be integrated with a fluorescentprotein (e.g., Green Fluorescent Protein (GFP)) or a fluorophore (e.g.,fluorophore based on quantum dot).

Furthermore, each separate strip/fluid cavity of themembrane/paper/polymer substrate can be integrated with an array oflarge numbers of three-dimensional protruded structures (e.g. plasmonicoptical nanoantennas or sharp tips) to significantly enhance thefluorescence (when activated by a light source) upon binding with thespecific disease protein, to fit at the binding site of the designerprotein with the specific leave-one-out configuration.

Early Point-of-Care Detection of a Disease with Exosomes andThree-Dimensional Protruded Structures

Serum can be separated from blood. Serum can be mixed and incubated at4° C. with System Bio Exoquick and further centrifuged and filtered toisolate exosomes. Furthermore, to obtain embedded proteins and RNAswithin the exosomes, a suitable chemical (e.g., System Bio company'sMicro SeraMir) can break the membrane of exosomes. Isolation of exosomescan be automated by a robotic tool.

A disease specific designer protein (integrated with a fluorescentprotein or a fluorophore) has a leave-one-out configuration, whereineach protein has an omitted segment to create a binding site to fit adisease specific protein, which was once caged within the exosomes.

Similarly, a disease specific aptamer (integrated with a fluorescentprotein or a fluorophore) can bind with a disease specific mRNA, whichwas once caged within the exosomes.

Light scattering and/or reflected fluorescence can detect/quantifydisease specific proteins and/or mRNAs, which were once gaged within theexosomes.

Plasmonic optical nanoantennas can be integrated with a fluorescentprotein or a fluorophore to enhance fluorescence. Alternatively,fluorescence can be magnified with an array of large numbers ofthree-dimensional protruded structures (e.g. plasmonic opticalnanoantennas or sharp tips) at or near the bottom floor of the fluidchamber, containing specific proteins and/or mRNAs and/or piRNAs whichwere once caged within the exosomes.

Measurement of fluorescence can be performed by the optical diagnosticbiomodule 700A (FIG. 9A), or 700C (FIG. 10A) or 700D (FIG. 11A) or 700E(FIG. 12A) or as illustrated in FIGS. 12V/12X1/12Y.

Early Point-of-Care Detection of a Disease with Exosomes,Microfluidic-Photonics Circuit (MPC) and Three-Dimensional ProtrudedStructures

Alternatively, in the first part, a microfluidic-photonics circuit chipcan take blood samples at inlets. The microfluidic-photonics circuitchip consists of a set of chambers molded in poly(dimethylsiloxane)(PDMS). The microfluidic-photonics circuit chip is degassed via vacuumprior to its use and the absorption of gas by poly(dimethylsiloxane)provides the mechanism for actuating and metering the flow of fluid inthe microfluidic channels and chambers.

In a second part, the microfluidic-photonics circuit chip can use tinymicrofluidic channels of 30 microns in diameter underneath the inlets toseparate the serum from the blood, by utilizing laws of microscalephysics. The serum moves through the microfluidic-photonics circuit chipvia a process called degas-driven flow.

Superparamagnetic nanoparticles of iron oxide can be synthesized with apositive electrical charge to bond onto the membrane surface of exosomes(exosomes are found within a human body's blood/biological fluid) ofnegative electrical charge due to electrostatic interactions. In a thirdpart, the microfluidic-photonics circuit chip can be integrated with amagnet. Exposure to a magnetic field can separate superparamagneticnanoparticles of iron oxide bonded with exosomes.

Alternatively, a third part of the microfluidic-photonics circuit chipcan be integrated with a nanosieve/nanomembrane (e.g., a carbonnanomembrane) of about 100 nanometers pore diameter to filter onlyexosomes.

Furthermore, a suitable chemical (e.g., System Bio company's MicroSeraMir) can be added in a fourth part of the microfluidic-photonicscircuit chip to break the membranes of exosomes to obtain embedded RNAsand proteins within the exosomes.

The fourth part of the microfluidic-photonics circuit has a diseasespecific aptamer (integrated with a fluorescent protein or afluorophore) to bind with a disease specific mRNA, which was once cagedwithin the exosomes.

Furthermore, the fourth part of the microfluidic-photonics circuit chiphas a disease specific designer protein (integrated with a fluorescentprotein or a fluorophore) with a leave-one-out configuration, whereineach protein has an omitted segment to create a binding site to fit adisease specific protein, which was once caged within the exosomes.

Light scattering and/or reflected fluorescence can detect/quantifydisease specific mRNAs and/or proteins which were once caged within theexosomes.

Plasmonic optical nanoantennas can be integrated with the fluorescentprotein or the fluorophore (e.g., quantum dot fluorophore) to enhancefluorescence.

Alternatively, the fourth part of the microfluidic-photonics circuit hasan array (e.g., billions) of large numbers of three-dimensionalprotruded structures (e.g. plasmonic optical nanoantennas or sharp tips)at or near the bottom floor of the fourth part of themicrofluidic-photonics circuit to enhance fluorescence.

In one instance, a modified microfluidic-photonics circuit chip withoutseparating the serum from a human body's blood can be utilized—thus theserum separation part is not needed. In this instance, the first part ofthe modified microfluidic-photonics circuit chip can contain a largearray of nickel coated superparamagnetic nanoparticles iron oxide/nickelcoated magnetic beads to detect malaria, as nickel chemically binds witha protein namely histidine-rich protein 2, produced by malaria in ahuman body's blood. It should be noted that face-centered tetragonalphase FePt alloy based magnetic bead can be as small as 3 nanometers.

The large array of nickel coated superparamagnetic nanoparticles ironoxide/nickel coated magnetic beads chemically bonded with histidine-richprotein 2 (produced by malaria) can be isolated by a magnet in thesecond part of the modified microfluidic-photonics circuit chip.

In the third part of the modified microfluidic-photonics circuit chip,contaminants on nickel coated superparamagnetic nanoparticles ironoxide/nickel coated magnetic beads chemically bonded with histidine-richprotein 2 (produced by malaria) can be washed.

The fourth part of the modified microfluidic-photonics circuit chipcontains a suitable salt solution to bind with nickel—thushistidine-rich protein 2 (produced by malaria) that can be detached.

The fifth part of the modified microfluidic-photonics circuit has adisease specific aptamer (integrated with a fluorescent protein or afluorophore) to bind with histidine-rich protein 2 (produced bymalaria).

Alternatively, in the fifth part of the modified microfluidic-photonicscircuit chip has a malaria disease specific designer protein (integratedwith a fluorescent protein or a fluorophore) with a leave-one-outconfiguration, wherein malaria disease specific designer protein has anomitted segment to create a binding site to fit with histidine-richprotein 2 (produced by malaria).

Light scattering and/or reflected fluorescence can detect/quantifyhistidine-rich protein 2 (produced by malaria).

Plasmonic optical nanoantennas can be integrated with the fluorescentprotein or the fluorophore (e.g., quantum dot fluorophore) to enhancefluorescence.

Alternatively, the fifth part of the modified microfluidic-photonicscircuit has an array of large numbers of three-dimensional protrudedstructures (e.g. plasmonic optical nanoantennas or sharp tips) at ornear the bottom floor of the fifth part of the modifiedmicrofluidic-photonics circuit to enhance fluorescence.

In another instance, a modified microfluidic-photonics circuit chipwithout separating the serum from a human body's blood can beutilized—thus the serum separation part is not needed. In this instance,the first part of the modified microfluidic-photonics circuit chip cancontain a large array of silica coated superparamagnetic nanoparticlesiron oxide/silica coated magnetic beads to detect tuberculosis, assilica chemically binds with the DNA of tuberculosis.

The large array of silica coated superparamagnetic nanoparticles ironoxide/silica coated magnetic beads chemically bonded with the DNA oftuberculosis can be isolated by a magnet in the second part of themodified microfluidic-photonics circuit chip.

In the third part of the modified microfluidic-photonics circuit chip,contaminants on silica coated superparamagnetic nanoparticles ironoxide/silica coated magnetic beads chemically bonded with the DNA oftuberculosis can be washed.

In The fourth part of the modified microfluidic-photonics circuit hasthe tuberculosis specific aptamer (integrated with a fluorescent proteinor a fluorophore) to bind with the DNA of tuberculosis.

Plasmonic optical nanoantennas can be integrated with the fluorescentprotein or the fluorophore (e.g., the quantum dot fluorophore) toenhance fluorescence.

Light scattering and/or reflected fluorescence can detect/quantify theDNA of tuberculosis.

Alternatively, the fourth part of the modified microfluidic-photonicscircuit has an array of large numbers of three-dimensional protrudedstructures (e.g. plasmonic optical nanoantennas or sharp tips) toenhance fluorescence.

Similarly, nickel coated superparamagnetic nanoparticles iron oxide(Fe₃O₄)/nickel coated magnetic beads, coupled with one or moresepsis-specific biomarker binders can filter sepsis from a human's bloodand filtered (sepsis free) human blood can be resupplied to a human.

X-Ray Fluorescence Diagnostic Biomodule Utilizing an Array ofMicrocapillaries & an Array of Miniature X-Ray Sources

An array of microcapillaries containing a biological sample can beexcited by an array of miniature x-ray sources (powered by the portableelectrical power providing component) to induce x-ray fluorescence inthe biological sample for various elemental concentrations related to adisease.

Furthermore, multiple DNAs and/or protein biomarkers can be detectedbased on characteristic x-ray fluorescence.

The array of sharp tips of a pyroelectric crystal (e.g., lithiumniobate/lithium tantalite) can be fabricated/constructed on a thin-filmresistor. The array of sharp tips can be capped with a metal thin-film.The metal thin-film emits x-rays when bombarded by electrons emitted bythe sharp tips.

The x-ray fluorescence can be detected by an array of silicon driftdetectors. Due to the unique process/fabrication technology of thesilicon drift detectors, the leakage current of the silicon driftdetectors is low such that the silicon drift detectors can be operatedwith a moderate cooling, provided by a single stage thermoelectriccooler (TEC)/microrefrigerator.

Furthermore, a high-efficiency nanostructure 50A° thick Sb₂Te₃/10A°thick Bi₂Te₃ based thin-film superlattices miniature thermoelectriccooler/microrefrigerator (about 1 millimeter×3 millimeters in size) canbe utilized to cool the array of silicon drift detectors.

However, significant thermoelectric cooler/microrefrigerator efficiencycan be gained by fabricating a quantum wire/quantum dot, transitioningfrom a two-dimensional superlattice.

Retinal Contact Lens Biomodule Subsystem for Detection of a DiseaseSpecific Biomarker/an Array of Disease Specific Biomarkers &Programmable/Active Delivery of Bioactive Compounds &/or BioactiveMolecules in Near Real-Time/Real-Time

Specific proteins (e.g., protein biomarkers of Alzheimer disease) canaccumulate in the retina. These specific proteins can be utilized todiagnose a disease specific biomarkers/an array of disease specificbiomarkers in near real-time/real-time.

FIG. 16A illustrates a retinal contact lens biomodule subsystem 1180 ona biocompatible frame 980.

The biocompatible frame 980 can be fabricated/constructed, utilizingliquid-crystal polymers/polyimide/silica/silicon/silk/SU-8 resin/othersuitable material.

Furthermore, if needed, the biocompatible frame 980 can be coated with afluorinated silicon material to protect against water and/or oil.

The retinal contact lens biomodule subsystem 1180 can integrate: (a) acontrol circuitry component 1000, (b) an array of display pixels 1020,(c) an array of microlenses 1040, (d) a biosensor component 1060, (e) abiosensor read-out component 1080, (f) a solar cell component 1120, (g)a micropatch component 1140, (h) a low-power wireless (radio)transmitter (with an antenna) component 1160 and (g) an electrical powerproviding component (e.g., a printed thin-film battery or an array ofglucose fuel cells) 400, utilizing a connecting electrical contact layer1100.

Example of a biosensor component 1060: Blood sugar measurement caninvolve an electrochemical reaction activated by an enzyme. Glucoseoxidase can convert glucose into hydrogen peroxide and otherchemicals—thus their concentrations can be measured with a miniaturepotentiostat or nanosized potentiostat as a biosensor for calculatingthe glucose level in tears. Furthermore, the biosensor component 1060can be integrated with an analog signal to a digital signal convertercircuit.

A glucose fuel cell consists of a platinum catalyst that stripselectrons from glucose-mimicking the activity of cellular enzymes thatbreak down glucose to generate adenosine triphosphate.

Multi-layers of positive electrical charged ferritin protein, separatedby a layer of nanocrystals, from multi-layers of negative electricalcharged ferritin protein—sandwiched between two (2) transparent metalelectrodes on a biocompatible substrate (e.g., silk) can act as thesolar cell component 1120.

Furthermore, the micropatch component 1140, can consist of porousnanoshells or nanodiamonds to deliver timolol maleate (which is commonlyused in eye drops) to manage glaucoma.

Printed Electronics Over a Three-Dimensional Structure forMiniaturization/Manufacturing of the Retinal Contact Lens BiomoduleSubsystem

Printed electronic technology or three-dimensional printing can print asection of the retinal contact lens biomodule subsystem 1180 over athree-dimensional structure, instead of assembling many discretecomponents. Higher levels of miniaturization and manufacturing can berealized, utilizing printed electronics (e.g., aerosol nanoparticle jetsto print an antenna, electronics circuitry, radio frequency componentand sensor) or three-dimensional printing.

The retinal contact lens biomodule subsystem 1180 can befabricated/constructed by lifting off the electronics circuit layer froma rigid semiconductor substrate and then bonding/connecting, the liftedoff electronics layer on nanoribbons of wires mounted onto a lightweightand stretchable membrane, wherein the wires can bend, twist and stretch,while maintaining their functionality.

Furthermore, the micropatch components 1140 can integrate amicroelectro-mechanical-system reservoir to store the bioactivecompounds 100 and/or bioactive molecules 100A for a sustained delivery.The above retinal contact lens biomodule subsystem 1180 can enable nearreal-time/real-time measurement of a disease specific biomarker andprogrammable/active delivery of the bioactive compounds 100 and/orbioactive molecules 100A in near real-time/real-time (via a dynamicclosed feedback loop).

FIG. 16B illustrates a near real-time/real-time application of awearable retinal contact lens biomodule subsystem 1180.

Near Real-Time/Real-Time Wearable Integrated Bioelectronics Subsystem,as an Augmented Reality Personal Assistant

FIGS. 17A, 17B, 17C, 17D and 17E illustrate a near real-time/real-timewearable bioelectronics subsystem 1580.

FIG. 17A illustrates a near real-time/real-time wearable subsystem 1540with a bifocal retinal contact lens 1180A on a biocompatible frame 980.

The bifocal retinal contact lens 1180A on the biocompatible frame 980has two (2) different focal lengths—one contact lens can focusforeground light into the middle of the pupil, while the other contactlens can focus the background light onto the edge of the pupil.Furthermore, the bifocal retinal contact lens 1180A can be embedded withoptical nanostructures to achieve higher optical performances.

The biocompatible frame 980 can be fabricated/constructed, utilizingliquid-crystal polymers/polyimide/silica/silicon/silk/SU-8 resin/othersuitable material.

Furthermore, if needed, the biocompatible frame 980 can be coated with afluorinated silicon material to protect against water and/or oil.

The bifocal retinal contact lens 1180A can be fabricated/constructed,utilizing liquid-crystal polymers/polyimide/silica/silicon/silk/SU-8resin/other suitable material. Furthermore, a photochromic transparentnanoemulsion polymer material can be used, which has an ability to blockglare by darkening immediately in strong sunlight and to revert back totransparency in normal sunlight. The photochromic transparentnanoemulsion polymer material also can offer ultraviolet-blockingability, high water content, oxygen permeability and suitable mechanicalproperties.

Furthermore, the bifocal retinal contact lens 1180A on the biocompatibleframe 980 can optionally integrate (a) a biosensor component 1060, (b)biosensor read-out component 1080 and (c) a micropatch component 1140 toenable near real-time/real-time measurement of a disease specificbiomarker and programmable/active delivery of the bioactive compounds100 and/or bioactive molecules 100A in near real-time/real-time (via adynamic closed feedback loop).

A common cause of blindness is when a retina is damaged by diseases thatkill the photoreceptors and/or destroy the circuits that create thecoded neural pulses. But often these diseases do not damage the outputcells. The bifocal retinal contact lens 1180A on the biocompatible frame980 can integrate (a) an artificial retina system which can consist ofan array of thin-film electrodes (in a biocompatible package) forstimulating the retina, a visual processing unit, a miniature videocamera and a transmitter mounted on an eye glass frame. The array of thethin-film electrodes should conform to the curvature of the retina.Thus, the array of thin-film electrodes should be fabricated/constructedon flexible polymers.

An artificial retina can require high-density electrical interconnectsbetween the array of the thin-film electrodes and a biocompatiblepackage.

The high-density electrical interconnects can be fabricated/constructed,utilizing an array of carbon fibers (about 10 microns in diameter),wherein each carbon fiber is coated with chemicals to prevent moisture,ionic and biological contamination from causing failure/damage of thecarbon fiber.

The high-density electrical interconnects can be insulated/hermeticallysealed in a biocompatible package (e.g., fabricated/constructed,utilizing polycrystalline diamond material) to prevent moisture, ionicand biological contamination from causing failure of the artificialretina.

The high-density electrical interconnects (integrated with the bifocalretinal contact lens 1180A) can convert/transform the electrochemicalsignals of eyes to digital signals of a localmicroprocessor/super-processor (including a graphical processing unit)1320 and vice-a-versa.

Similarly, the high-density electrical interconnects integrated with aneural converter chip (which can be implanted in a human brain) toconvert/transform electrochemical signals of a human brain to digitalsignals for coupling with a local microprocessor/super-processor(including a graphical processing unit) 1320 and/or coupling with one ormore artificial neural network based neural processors in a cloud serverand vice versa.

A light pattern incident to the artificial retina can be converted intoa set of mathematical equations/codes of electrical patterns. An encoderchip can convert a general light pattern (incident on a retina) into aset of mathematical equations/codes of an electrical pattern.

A miniaturized projector-decoder chip can convert the above electricalpattern into a modified coded light pattern to drive the light-sensitiveproteins (these light-sensitive proteins can be delivered by thenanoshell 120 and/or by gene therapy in the ganglion cells) to themodified light pattern to a human brain, which understands the stream ofcoded light patterns to translate into meaningful images.

Furthermore, an encoder circuit, a decoder circuit and a biocircuit (abiocircuit fabricated/constructed, utilizing DNA, RNA and a protein torespond to biological signals) can be integrated in the biocompatiblepackage.

Alternatively, a retinal implant microchip can be used below the fovea(area of sharpest vision in the retina). The retinal implant microchipis approximately 3 millimeters×3 millimeters in area and 50 microns inthickness. The retinal implant microchip has about 1500 pixels, whereineach pixel has an area of about 75 microns×75 microns. An array ofphotocells (e.g., a light dependant resistor/light dependantphototransistor), an amplifying circuit, a stimulation electrode, anencoder circuit and a decoder circuit are integrated with each pixel.The photocells absorb the light entering the eye, transforming the lightinto electrical signals. The retinal implant microchip can beelectrically powered by a subdermal coil behind the ear. The subdermalcoil can be electrically powered by a battery via transdermal inductivetransmission.

Furthermore, in the case of blindness caused by destroyedphotoreceptors, suitable light sensitive proteins can be delivered bythe nanoshell 120 and/or by gene therapy, so that sensitive proteins canchemically bind with remaining bipolar cells, wherein the bipolar cellsare located below the destroyed photodetectors. These suitable lightsensitive proteins can interact with an array of nano-scaled cameras tocommunicate with the ganglion cells for restoring vision, at least in alimited way. By way of an example and not by way of any limitation,Light Harvesting Complex II proteins of spinach can be utilized assuitable light sensitive protein.

Additionally, interactions of photons (of various wavelengths) withlight sensitive protein(s) chemically bonded with cells (e.g., neurons)can be utilized to model treatment (with bioactive compounds 100 and/orbioactive molecules 100A) efficiency for various diseases (e.g.,neurological diseases).

FIG. 17B illustrates a power unit 400, a storage/memory component 880, awireless transceiver (e.g., a radio/millimeter wave (including 60GHz)/terahertz band) with an antenna 900, a control circuitry component1000, a microphone 1200, a scrolling audio recording buffer 1220, acamera (e.g., a holographic camera/three-dimensional computational imagecamera, utilizing a light-field camera, capturing intensity and arrivalangles of light rays) with a built-in sensor 1240, a locationdetermination component (e.g., an indoor positioning system (IPS)/globalpositioning system (GPS)) 1260 and a first PCS component (a PCS is anintegration of a projector, a camera and an emotion sensor/eyemotion/gesture/touch sensor) component 1280 embedded in the eye glassframe.

Furthermore, Broadcom's BCM4752 chipset can support an indoorpositioning system with Bluetooth, Wi-Fi and near-field communication.

The powering unit 400 can be a nanobattery or a wireless enabledpowering unit.

FIG. 17B also illustrates an array of display pixels (e.g., pixels ofliquid-crystal display (LCD)/light emitting display (LED)/organic lightemitting display (OLED)/quantum dots based display) 1020 covering abouthalf of the eye glass, displaying an instant live action (e.g., a livesurgery or a car race illustrated as in FIG. 17C) or a physicalenvironment, an electrical contact layer/thread (e.g., super-strongelectrically conducting DuPont Aracon-made of Kevlar clothing fiber)1100, a solar cell component 1120 on the corners of the eye glasses(optionally the solar cell component 1120 can be located anywhere on theframe, rather than on the corners of the eye glasses), an integrated eyetracking sensor and decoder 1300, at the enter of the eye glass frame.

Light emitting diode/organic light emitting diode display/quantum dotsbased display is limited to a few pixels, but liquid-crystal displayscan permit a larger surface.

A spherical curved liquid-crystal display based on an array of displaypixels 1020 can enable text, images, videos and other visuals on thespherical curved liquid-crystal display.

Furthermore, liquid-crystal display based on an array of display pixels1020 can be an array of three-dimensionally configured liquid-crystaldisplay pixels. Details of three-dimensionally configured liquid-crystaldisplay pixels are described in later paragraphs.

The display/display pixels 1020 (including three-dimensionallyconfigured liquid-crystal display pixels) can be integrated with anarray of sensors, such sensors can be fabricated/constructed (e.g.,optically sensing waveguides) by a femtosecond laser. Utilizing afemtosecond laser module, a two-dimensional/three-dimensional opticallysensing waveguide(s) can be fabricated/constructed at various depths ofthe display substrate. For example, such sensors can enable detection ofa near real-time/real-time image or an environment near the user'slocation. The substrate of the display incorporating display pixels 1020can be integrated with a metamaterial surface (utilizing many opticalnanoantennas) to enable a three-dimensional/holographic display. Detailsof a three-dimensional/holographic display/real-time holographic display(with micro-scaled pixels) have been described/disclosed in U.S.Non-Provisional patent application Ser. No. 14/999,601 entitled “SYSTEMAND METHOD OF AMBIENT/PERVASIVE USER/HEALTHCARE EXPERIENCE”, filed onJun. 1, 2016 and the entire contents of this US Non-Provisional PatentApplication are incorporated herein.

The display incorporating display pixels 1020 can be integrated with (a)a transparent/semi-transparent image sensor (e.g.,transparent/semi-transparent sensor based on graphene), (b) atransparent/semi-transparent microprocessor based on nanowires (e.g.,zinc oxide nanowires), (c) a transparent/semi-transparent memory and (d)a transparent/semi-transparent battery/solar cell. It should be notedthat the transparent/semi-transparent image sensor,transparent/semi-transparent microprocessor,transparent/semi-transparent memory and transparent/semi-transparentbattery/solar cell are not needed in some cases, unless they arefabricated/constructed/packaged directly on the display incorporatingdisplay pixels 1020.

An ultrafast transparent/semi-transparent memory of grapheneoxide-titanium oxide dual-layer memory cell (about 25 nanometres longand 4 nanometres thick) can be utilized. The display can be integratedwith transparent/semi-transparent solar cell (e.g., CH₃NH₃PbI₃-xClxperovskite based solar cell, utilizing indium tin oxide (ITO) orfluorine-doped tin oxide (FTO) and gold or graphene electrode).Furthermore, the transparent/semi-transparent solar cell can beintegrated with vanadium dioxide nanoparticles/thin-film for bothelectricity generation and electricity saving. Additionally, atransparent luminescent solar concentrator device of organic moleculescan be utilized to absorb invisible wavelengths of light (e.g.,ultraviolet and/or near infrared) and then to concentrate at the edge ofthe transparent luminescent solar concentrator device, wherein an arrayof strips of photovoltaic solar cells can convert solar energy toelectricity. Details of such configuration been described/disclosed inU.S. Non-Provisional patent application Ser. No. 14/999,601 entitled“SYSTEM AND METHOD OF AMBIENT/PERVASIVE USER/HEALTHCARE EXPERIENCE”,filed on Jun. 1, 2016 and the entire contents of this US Non-ProvisionalPatent Application are incorporated herein.

Furthermore, a perovskite containing both inorganic materials (iodineand lead) and an organic material (methyl-ammonium) can boost solar toelectric conversion efficiency.

Additionally, the transparent/semi-transparent microprocessor can beintegrated with an array of transparent/semi-transparent sensors (e.g.,transparent vanadium dioxide/bismuth ferrite based sensors). Suchtransparent/semi-transparent sensors integrated with thetransparent/semi-transparent microprocessor can sense, manipulate andrespond quickly, because either feedback or feed forward control isintegrated within one integrated system-on-chip.

A graphene (with both source metal and drain metal on graphene, grapheneis fabricated/constructed on silicon carbide) based field effectphototransistor can be utilized to detect a change in electric field,caused by light, interacting with an undoped silicon carbide substrate(with back gate metal). An array of pixels of graphene based fieldeffect transistors can be utilized for an ultrasensitive camera sensor,which can be integrated with a see-through display (e.g., an organiclight-emitting display) incorporating display pixels 1020.

The thin-film transistor (TFT) located at each display pixel 1020 cancontrol an image at each display pixel 1020 of the display. However, thethin-film transistor can also have a light sensing circuitry to sensethe light reaching the pixels 1020 of the display from itssurroundings—thus enabling the possibility of new user experience withthe display pixel 1020 of the display. Furthermore, the displayincorporating the display pixels 1020 can enable a dual-view to showentirely two separate scenes simultaneously. Both light sensing displaypixels and dual-view display have been described/disclosed in U.S.Non-Provisional patent application Ser. No. 13/448,378 entitled “SYSTEMAND METHOD FOR MACHINE LEARNING BASED USER APPLICATION”, filed on Apr.16, 2012 and the entire contents of this US Non-Provisional PatentApplication are incorporated herein.

Thus, the display incorporating the display pixels 1020 can beintegrated with (a) dual-view to show entirely two separate scenessimultaneously and/or, (b) a light sensing circuitry to sense the lightreaching the pixels 1020 of the display and/or, (c) a solar cell and/or,(d) a camera sensor and/or, (e) a sensor and/or, (f) atransparent/semi-transparent microprocessor and/or, (g) atransparent/semi-transparent memory and/or (h) a network of photonicintegrated circuits (as described in later paragraphs), wherein (b),(c), (d), (e), (f) and (g) can be connected by a small area electricalinterconnect and optical interconnect or by an electro-opticalinterconnect (the electro-optical interconnect can be realized byplurality of semiconductor fibers (a semiconductor fiber consists ofdepositing/laser recrystallizing an amorphous semiconductor materialinto core of silica fiber for propagation of both light andelectricity).

Additionally, the display incorporating display pixels 1020 can beintegrated with a partially reflective multi-layer thin-film coating tosee-through/view-through. The display pixels 1020 can betouch-sensitive. Details of see-through/view-through configuration havebeen described/disclosed in U.S. Non-Provisional patent application Ser.No. 14/999,601 entitled “SYSTEM AND METHOD OF AMBIENT/PERVASIVEUSER/HEALTHCARE EXPERIENCE”, filed on Jun. 1, 2016 and the entirecontents of this US Non-Provisional Patent Application are incorporatedherein.

The display incorporating display pixels 1020 can be integrated with avanadium dioxide thin-film thermochromic device, when it is activated byeither voltage or temperature.

Alternatively, the glass material for the display pixels 1020 can bereplaced by a super-strong, scratch-resistant and bendable (about 0.5millimeters in thickness) plastic. The plastic has a fingerprint proofmaterial layer at the front and a polymer hardening material layer atthe back.

Alternatively, thin-film transistor-organic light emitting diode(TFT-OLED) display pixels 1020 can enable text, images, videos and othervisuals on the spherical curved thin-film transistor-organic lightemitting diode display pixels 1020.

Furthermore, thin-film transistor can be either organic transistor basedor carbon nanotube based. Carbon nanotube based thin-film transistor canbe fabricated/constructed by the gravure printing method, where aplastic substrate is mounted onto a cylindrical drum, which rolls itover a flat surface that serves as a patterned mask of holes filled withinks made of the desired materials. The gravure printing method can beprocessed at a relatively low temperature, making it suitable with aplastic substrate. The gravure printing method can be utilized tofabricate/construct various sensors/micro-scaled sensors/nano-scaledsensors. Thus, each thin-film transistor-organic light emitting diodedisplay pixel 1020 can be integrated or embedded with asensor/micro-scaled sensor/nano-scaled sensor.

The display pixel related circuits using conventional thin-filmtransistors are slow for any real-time tasks. But graphene conductselectricity faster than silicon. By chemically flaking graphene,filtering it and using N-Methylpyrrolidone, transparent graphene baseddisplay pixel related circuits can be printed through a conventionalinkjet printer.

FIG. 17B also illustrates a second PCS component 1280 and themicroprocessor/super-processor (including a graphical processing unit)1320 comprised or connected or electrically/wirelessly coupled with anoperating system algorithm 920 on the right frame. The system operatingalgorithm 920 can be located at the storage/memory component 880 or in acloud based data storage unit to interact with the localmicroprocessor/super-processor (including a graphical processing unit)1320.

Furthermore, various embodiments of (a) displays/holographic displays,(b) viewing/partial viewing configurations and (c) system-on-chips(including neural networks based system-on-chips) related to the nearreal-time/real-time wearable subsystem 1540 have beendescribed/disclosed in U.S. Non-Provisional patent application Ser. No.14/999,601 entitled “SYSTEM AND METHOD OF AMBIENT/PERVASIVEUSER/HEALTHCARE EXPERIENCE”, filed on Jun. 1, 2016 and the entirecontents of this US Non-Provisional Patent Application are incorporatedherein.

The above system-on-chip can be a neural learning processor (eitherelectrical or photonics based) and it can replace themicroprocessor/super-processor (including a graphical processing unit)1320 and also enable cognitive/neural like computing for learning orrelearning.

Furthermore, it should be noted that the above cognitive/neural likecomputing for learning or relearning can be enhanced by an intelligentlearning algorithm 1460 (stored in a storage/memory component 880 or ata cloud based data storage unit or a cloud based server) and/oraugmented by an implanted neural converter chip to convert/transformelectrochemical signals of a human brain to digital signals of a localmicroprocessor/super-processor (including a graphical processing unit)1320 and vice-a-versa.

Furthermore, the operating system algorithm 920 can be integrated with avoice recognition/editing algorithm 1340, a voice-to-text conversionalgorithm 1360, an algorithm to decipher and understand a sound 1380, agesture (to interpret body movements by embedded sensors in a peripheraldevice (e.g., a stylus/body wear)) a recognition algorithm 1400, aface/emotion recognition algorithm 1420, a pattern recognition algorithm1440, an intelligent learning algorithm 1460 and a software agent 1480.

The intelligence from the intelligent learning algorithm 1460 can becoupled with a data mining algorithm and a predictive modelingalgorithm. Both the data mining algorithm and predictive modelingalgorithm can reside in a cloud based data storage unit to interact withthe intelligent learning algorithm 1460.

Additionally, the voice recognition/editing algorithm 1340, thevoice-to-text conversion algorithm 1360, the algorithm to decipher andunderstand a natural language/sound 1380, the algorithm to understandgesture (to interpret body movements by embedded sensors in a peripheraldevice (e.g., a stylus/body wear)) 1400, the face/emotion recognitionalgorithm 1420, the pattern recognition algorithm 1440, the intelligentlearning algorithm 1460 and the software agent 1480 can reside at thestorage/memory component 880 or in a cloud based data storage unit tointeract with the local microprocessor/super-processor (including agraphical processing unit) 1320 and derive intelligence synthesized fromvast amounts of data patterns.

It should be noted that the intelligent learning algorithm 1460 caninclude or couple with artificial intelligence (including self-learningartificial intelligence), computer vision (including self-learningcomputer vision), data mining, fuzzy/neuro-fuzzy logic, machine vision(including self-learning machine vision), natural language processing,neural networks (including self-learning neural networks), patternrecognition, reasoning modeling and self-learning (including evidencebased self-learning), stored in a cloud based data storage unit/cloudbased server to interact with the local microprocessor/super-processor(including a graphical processing unit) 1320 and derive intelligencesynthesized from vast amounts of data patterns

It should be noted that artificial intelligence (including self-learningartificial intelligence), computer vision (including self-learningcomputer vision), data mining, fuzzy/neuro-fuzzy logic, machine vision(including self-learning machine vision), natural language processing,neural networks (including self-learning neural networks), patternrecognition, reasoning modeling and self-learning (including evidencebased self-learning) can be enhanced by quantum computing or quantumcomputing based machine learning based algorithm, stored in a cloudbased data storage unit/cloud based server.

Additionally, many components can be integrated within a plastic/polymerlayer (e.g., super-strong electrically conducting DuPont Aracon—made ofKevlar clothing fiber).

As illustrated in FIG. 17D, stacking circuits of themicroprocessor/super-processor (including a graphical processing unit)1320 in three-dimension can be achieved by utilizing a large array ofvertical nanotubes (e.g., a boron nitride/carbon nanotubes) 1480 and ahorizontal frame 1500 of a two-dimensional material (e.g.,graphene/molybdenum disulphide) or silicene with an electrical circuit1520 and memristor 1540—thus substantially eliminating interconnectedwires.

For example, memristor 1540 can be fabricated/constructed, assilver/amorphous-silicon/poly-silicon structure. Furthermore, aparticular phase change material-Ag₄In₃Sb₆₇Te₂₆ can switch between adisordered amorphous phase A and another disordered amorphous phase B ina sub-picosecond time-scale, when excited by picosecond electricalpulses (e.g., about 500 kV/cm peak field strength at a repetition rateof about 30 Hz for about 30 seconds). Such phase change switching occursat lower electric field strength/energy level and such ultra-fast phaseswitching can enable an ultra-high speed non-volatile memristor(s) (asswitching from the disordered amorphous phase B to the disorderedamorphous phase A back requires an application of a short burst of heat,which can be provided electrically/optically).

Furthermore, a large array of vertical nanotubes (e.g., boronnitride/carbon nanotube) grown on a two-dimensional material-grapheneinterface chemically bonded on a diamond substrate can act as achip-to-chip interconnect, as well as a heat sink.

Alternatively, the vanadium dioxide or vanadium(III) oxide based opticalswitch can be utilized as a chip-to-chip interconnect. Details of anembodiment of a chip-to-chip interconnect have been illustrated in FIG.21A of U.S. Non-Provisional patent application Ser. No. 13/448,378entitled “SYSTEM & METHOD FOR MACHINE LEARNING BASED USER APPLICATION”,filed on Apr. 16, 2012 and have been described/disclosed in U.S.Non-Provisional patent application Ser. No. 14/999,601 entitled “SYSTEMAND METHOD OF AMBIENT/PERVASIVE USER/HEALTHCARE EXPERIENCE”, filed onJun. 1, 2016 and the entire contents of this US Non-Provisional PatentApplication are incorporated herein.

Stacking circuits of the microprocessor/super-processor (including agraphical processing unit) 1320 in a three-dimensional configuration canbe achieved, by utilizing droplets of nanoparticle-infused liquid,thus-substantially eliminating interconnect wires.

Furthermore, stacking circuits of the microprocessor/super-processor(including a graphical processing unit) 1320 in a three-dimensionalconfiguration can be also achieved by DNA/RNA template wires for anano-scaled circuit board—thus substantially eliminating interconnectwires.

The bifocal retinal contact lens 1180A and some components of a device1560 can be integrated on a common biocompatible substrate. The bifocalretinal contact lens 1180A with the device 1560 is a nearreal-time/real-time wearable integrated bioelectronics subsystem 1580.

The near real-time/real-time wearable integrated bioelectronicssubsystem 1580 can couple or integrate with a nano-scaled system. Such anano-scaled system can include: (a) a nanoprocessor (e.g., molybdenumdisulphide nanoprocessor), (b) a nanomemory/nanostorage (e.g., amemristor 1540 based nanomemory/nanostorage), (c) a nanoradiotransceiver with a nanoantenna (e.g., graphene based nanoantenna) and(d) a nanosensor, wherein the nanoprocessor and nanomemory arewirelessly connected for data bus by the nanoradio transceiver with thenanoantenna. A nanobattery or a wireless enabled powering unit canelectrically power the nano-scaled system. Details of the nano-scaledsystem have been described/disclosed in U.S. Non-Provisional patentapplication Ser. No. 14/999,601 entitled “SYSTEM AND METHOD OFAMBIENT/PERVASIVE USER/HEALTHCARE EXPERIENCE”, filed on Jun. 1, 2016 andthe entire contents of this US Non-Provisional Patent Application areincorporated herein.

Furthermore, the near real-time/real-time wearable integratedbioelectronics subsystem 1580 can assist in memory recollection forpatients with Alzheimer's disease.

FIGS. 17A, 17B, 17C, 17D and 17E illustrate the near real-time/real-timewearable integrated bioelectronics subsystem 1580, which can act as anaugmented reality personal assistant to (a) eavesdrop on a user'scommunication (e.g., an e-mail/text/image/sensing/viewing), (b) searchthe internet with or without (anonymously) the user's input and (c) thenrecommend a solution to the user's need (utilizing the intelligentlearning algorithm 1460, integrated with a predictive modelingalgorithm) in near real-time/real-time.

Furthermore, the camera with a sensor 1240 is configured to track theuser's hands for sensing; when the user touches anything, along with themicrophone 1200 to capture the user's voice for spoken commands.

The integrated eye tracking sensor and decoder 1300 can be configured todetect a radio frequency identification/near-field communication tag orrecognize an optical identification (e.g., a barcode/quick responsecode).

Furthermore, the integrated eye tracking sensor and decoder 1300 can beconfigured to communicate with other sensors (e.g., bio/health sensors)in near real-time/real-time.

For example, the integrated eye tracking sensor and decoder 1300 of thenear real-time/real-time integrated bioelectronics wearable subsystem1580, as an augmented reality personal assistant can detect the user'seye position to pinpoint an item/person that the user is focused on.

The integrated eye tracking sensor and decoder 1300 can then read anitem/person in the user's field of view and convert/record the readinginto a text/image/holographic image as a location based nearreal-time/real-time snapshot/holographic snapshot of the contextualworld around the user.

Additionally, an indoor positioning system can track/map how and wherethe user spends his/her time both online and offline and if these timesare happy or sad. Furthermore, an indoor positioning system can linklocation, payment pattern and personal analytics of the user in nearreal-time/real-time or depicting the user's daily life in nearreal-time/real-time (“social graph”). It should be noted that socialgraph is synonymous with personal analytics.

The near real-time/real-time wearable integrated bioelectronicssubsystem 1580, as an augmented reality personal assistant (integratedwith an indoor positioning system) is with the user all the time and italready contains a host of personal information/data/preference and itcan manage daily aspects of the user's life, utilizing an intelligentweb portal (“social wallet”). Details of a social wallet have beendescribed/disclosed in U.S. Non-Provisional patent application Ser. No.13/448,378 entitled “SYSTEM & METHOD FOR MACHINE LEARNING BASED USERAPPLICATION”, filed on Apr. 16, 2012 and the entire contents of this USNon-Provisional Patent Application are incorporated herein.

For example, by eavesdropping on the user's communication, the nearreal-time/real-time wearable integrated bioelectronics subsystem 1580,as an augmented reality personal assistant can anticipate the user'sneed for emergency healthcare and then recommend the fastest route tothe emergency section of a nearby hospital by synthesizing data(anonymously searching the internet) regarding traffic, road and weathercondition. If the user is about to go to the emergency section of anearby hospital, but another healthcare facility is cheaper with aspecial offer, the near real-time/real-time wearable integratedbioelectronics subsystem 1580, as an augmented reality personalassistant can alert the user. Again, this can be achieved passively,without giving away the user's location.

Furthermore, the near real-time/real-time wearable integratedbioelectronics subsystem 1580, as an augmented reality personalassistant can enable the user to share location based nearreal-time/real-time snapshots/holographic snapshots of the contextualworld around the user—a way of viewing the world through someone else'seyes on his/her way to a place/event.

FIG. 17E illustrates a power skin with a thin-film printed battery or atextile nanogenerator, integrated with a textile supercapacitor (forenergy storage).

Prestin protein is found in the outer hair cells of a human ear. Prestincan convert tiny vibrations into a voltage. To increase conductivity, amicrobe (e.g., a bacterium Pili) can act as a conducting nanowire totransfer electrons generated by prestin. Each protein is capable ofmaking nanowatts of electricity, but an array of prestin proteins cancharge a battery. Furthermore, networks of the prestin proteins canconstruct a nanogenerator on the power skin, so that the user's naturalmovements can generate electrical power. The user's natural movementscan generate electrical power in an embedded textile battery (e.g.,piezoelectric zinc oxide nanowires woven in textile-fibers). Annealed(at about 125° C.)/self-assembled (aqueous-dried) thin-film ofelectrically conducting vanadium pentoxide (V₂O₅) fibers (with ionsincorporated between the vanadium pentoxide fibers) can be utilized as asuitable electrically conducting fiber electrode for the power skin. Theelectrical properties and mechanical properties of annealed (at about125° C.)/self-assembled (aqueous-dried) thin-film of electricallyconducting vanadium pentoxide fibers can vary according to the amount ofwater content. A direct synthesis of multi-layer graphene and porouscarbon woven composite films by chemical vapor deposition on Ni gauzetemplates can be achieved. The composite films integrate the dualadvantages of graphene and porous carbon, having not only the excellentelectrical properties and flexibility of graphene, but also the porouscharacteristics of amorphous carbon. The multi-layer graphene/porouscarbon woven fabric film can enable a textile supercapacitor.

Furthermore, the power skin can be integrated with a component to detecta radio frequency identification/near-field communication tag or torecognize an optical identification (e.g., a barcode/quick responsecode).

The near real-time/real-time wearable integrated bioelectronicssubsystem 1580, as an augmented reality personal assistant can (a)determine the location of the user, (b) upload near real-time/real-timesnapshots/holographic snapshots of the contextual world around the userto a cloud based data storage unit and (c) instantly share locationbased near real-time/real-time snapshots/holographic snapshots of thecontextual world around the user's near real-time/real-time wearableintegrated bioelectronics subsystem 1580, as an augmented realitypersonal assistant with another user's near real-time/real-time wearableintegrated bioelectronics subsystem 1580, as an augmented realitypersonal assistant and/or another user's portable internet appliance,wherein the portable internet appliance can be connected with anobject/an array of objects, wherein the object is fabricated/constructedwith at least a sensor and a wireless transmitter.

Additionally, the components of the object can be packaged by aredistributive chip packaging (RCP) method.

The near real-time/real-time wearable integrated bioelectronicssubsystem 1580, as an augmented reality personal assistant can enable apay-per-gaze advertising model that involves billing an advertiser, ifthe user looks at an ad online or offline, while wearing the nearreal-time/real-time wearable integrated bioelectronics subsystem 1580.

Furthermore, the near real-time/real-time wearable integratedbioelectronics subsystem 1580, as an augmented reality personalassistant can enable a pay-per-interact advertising model that involvesbilling an advertiser, if the user interacts with an ad online oroffline, while wearing the near real-time/real-time wearable integratedbioelectronics subsystem 1580.

The near real-time/real-time wearable integrated bioelectronicssubsystem 1580, as an augmented reality personal assistant can enable anapplication (e.g., navigation, photo capture and sharing information).Thus, a surgeon can have a patient's vital information in front ofhis/her eyes, while operating on the patient.

The near real-time/real-time wearable integrated bioelectronicssubsystem 1580, as an augmented reality personal assistant can enablethe user to interact with virtual items, as the camera with a built-insensor 1240 is configured to track hands for sensing; when the usertouches anything along with the microphone 1200 to capture the user'svoice for spoken commands in a natural language.

Furthermore, the near real-time/real-time wearable bioelectronicssubsystem 1580, as an augmented reality personal assistant can beintegrated with a headset to block out all external light—thus enablinga high-definition image (in front of the user's eyes) for an immersiveexperience. The headset can be synchronized with the nearreal-time/real-time wearable bioelectronics subsystem 1580 to track theuser's head movement and/or eye movement. For example, the nearreal-time/real-time wearable bioelectronics subsystem 1580 can beutilized for e-mails, text messages, Facebook/Twitter updates, tweets,appointments & incoming phone calls, breaking news, weather, stock data,sports results, real-time feedback on action sports, turn by turndirections, aid for hearing impaired, translations when talking indifferent languages, patient's body data to a surgeon, remote trainingfor surgery, teleprompter for public speaking, subtitles at the movies(for hearing impaired and/or for different languages),teaching/discovery, details about art in a museum, social graph/personalanalytics and gaming.

A blockchain is a global distributed ledger/database running on millionsof devices and open to anyone, involving not just information butanything of value. In essence, it is a shared trusted public ledger thateveryone can inspect, but which no single user controls. A blockchaincreates distributed documentation of (outputs/transactions) in the formof a digital ledger available on a network of computers. When atransaction happens, the users propose a record to the ledger. Recordsare bundled into blocks (groups for processing), and each block receivesa unique fingerprint derived from the records it contains. Each blockcan include the fingerprint of the prior block, creating a robust chainof title. It's very easy to verify the integrity of the entire chain,and nearly impossible to falsify historic records. In summary, ablockchain is a public ledger of transactions which critically providestrust based upon mathematics, rather than human relationships orinstitutions. Furthermore, a blockchain can be a public blockchain or aconsortium blockchain or a private blockchain.

FIG. 17E illustrates interactions/communications/couplings of the nearreal-time/real-time wearable bioelectronics subsystem 1580, as anaugmented reality personal assistant with (a) another nearreal-time/real-time wearable bioelectronics subsystem, as an augmentedreality personal assistant and (b) the portable internet appliance 1600via a cloud based data storage unit. It should be noted that the nearreal-time/real-time wearable bioelectronics subsystem 1580, as anaugmented reality personal assistant can directlyinteract/communicate/couple with the portable internet appliance 1600and/or the near real-time/real-time wearable bioelectronics subsystem1580, as an augmented reality personal assistant via the internet forsharing snapshots/holographic snapshots (e.g., images/videos) of thesurrounding contextual world. The user may colorenhance/edit/geotag/personalize (e.g., personalize with emoji/emoticon)snapshots/holographic snapshots by utilizing an algorithm(s). Forexample, the user is watching the 2016 NBA final game between theCleveland Cavaliers v. Golden State Warriors, the user (along withhis/her personalized social graph and/or social geotag of geographicaldata (latitude & longitude) with videos, photographs, websites, e-mailsand status updates) may color enhance/edit/geotag/personalize the nearreal-time/real-time snapshots/holographic snapshots of Lebron Jamesblocking the shot of the Golden State Warriors' Andre Iguodala like“unbelievable—superman/batman performance of Lebron James” by eithertext input or text command in natural language or voice command innatural language from the near real-time/real-time wearablebioelectronics subsystem 1580, as an augmented reality personalassistant or from the portable internet appliance 1600.

Furthermore, the near real-time/real-time wearable bioelectronicssubsystem 1580, as an augmented reality personal assistant can be alsoelectrically or wirelessly coupled with networks of objects/biologicalobjects, which can couple with a blockchain to manage theiroutputs/interactions. Networks of objects/biological objects can enablea highly distributed global grid, wherein blockchain enabledtransactions can be negotiated by one or more machine learning/deeplearning neural networks based learning/relearning algorithms and can beexecuted for self-executing and self-enforcing smart contracts. Thesetransactions can be verified by the many near real-time/real-timewearable bioelectronics subsystem 1580 s, as an augmented realitypersonal assistants. Biological programming (e.g., editing a gene of aspecific cell for a specific function) is a biological transaction,which can be provisioned, regulated and supported by a blockchain. Forexample, networks of objects/biological objects can report to ablockchain, when it detects a problem. The problem can trigger a set ofinstructions (e.g., calling/paying for repairman/doctor) for solving thespecific problem, even before the user knows anything is wrong.

The near real-time/real-time wearable bioelectronics subsystem 1580, asan augmented reality personal assistant with an internet connection,real-time location data, personal information/profile,appointments/calendar, chats/e-mails (or eavesdropping onchats/e-mails/conversations in a natural language in nearreal-time/real-time), payment/purchase history and a changing socialgraph (of the user) can anticipate what information the user may/willneed based on context and past behavior—thus to provide it, before theyhave even asked for it. For example, spontaneously and predictivelysuggesting that the user should stay in the hotel room, because of heavytraffic in the downtown of a city (where the hotel is located) and offerpersonalized suggestions for a dinner in the hotel.

The near real-time/real-time wearable bioelectronics subsystem 1580, asan augmented reality personal assistant with an internet connection,real-time location data, personal information/profile,appointments/calendar, chats/e-mails (or eavesdropping on chats/e-mailsin near real-time/real-time), payment/purchase history and a changingsocial graph (of the user) can eavesdrop on the user's communication,utilizing (a) an intelligent learning algorithm and/or (b) an algorithmfor understanding communication, wherein the intelligent learningalgorithm and/or the algorithm for understanding communication can bestored in the storage/memory component 880 or a cloud based data storageunit.

In connection with (a) another near real-time/real-time wearablebioelectronics subsystem 1580, as an augmented reality personalassistant and (b) the portable internet appliance via a cloud based datastorage unit, the near real-time/real-time wearable bioelectronicssubsystem 1580, as an augmented reality personal assistant with aninternet connection, real-time location data, personalinformation/profile, appointments/calendar, chats/e-mails (oreavesdropping on chats/e-mails/conversations in a natural language innear real-time/real-time), payment/purchase history and a changingsocial graph (of the user) can anticipate what information the usermay/will need based on context and past behavior—thus to provide it,before they have even asked for it. For example, spontaneously andpredictively suggesting that the user buy a new dress with particulardetails (e.g., matching colors), prior to a job interview and offerpersonalized suggestions for the new dress.

Furthermore, the near real-time/real-time wearable bioelectronicssubsystem 1580, as an augmented reality personal assistant can detectwhat's going on in a photo or video, live in real-time, making itpossible to suggest contextual choice recommendations for thatparticular situation, when the near real-time/real-time wearablebioelectronics subsystem 1580, as an augmented reality personalassistant communicates with an unified algorithm, wherein the unifiedalgorithm can include artificial intelligence (including self-learningartificial intelligence), computer vision (including self-learningcomputer vision), data mining, fuzzy/neuro-fuzzy logic, machine vision(including self-learning machine vision), natural language processing,neural networks (including self-learning neural networks), patternrecognition, reasoning modeling and self-learning (including evidencebased self-learning).

Furthermore, a location-sensing system, utilizing sensors (which arecapable of area sensing, depth sensing and motion tracking), computervision (including self learning computer vision), machine vision(including self-learning machine vision), image processor and/or themicroprocessor/super-processor (including a graphical processing unit)1320 can enable the near real-time/real-time wearable bioelectronicssubsystem 1580, as an augmented reality personal assistant nearreal-time/real-time comprehension of space and motion forlearning/remembering/mapping areas around the near real-time/real-timewearable bioelectronics subsystem 1580, as an augmented reality personalassistant. It should be noted that the system-on-chips (including neuralnetworks based system-on-chips) described/disclosed in U.S.Non-Provisional patent application Ser. No. 14/999,601 entitled “SYSTEMAND METHOD OF AMBIENT/PERVASIVE USER/HEALTHCARE EXPERIENCE”, filed onJun. 1, 2016 can replace the above microprocessor/super-processor(including a graphical processing unit) 1320 and also enablecognitive/neural like computing and the entire contents of this USNon-Provisional Patent Application are incorporated herein.

For example, a virtual reality game (e.g., Pokémon Go) can appear inclose proximity and really interact with its environment/landscape in arealistic way, rather than hovering just in the air. An artist islivestreaming a performance, which can be watched by the nearreal-time/real-time wearable bioelectronics subsystem 1580, as anaugmented reality personal assistant. The artist can receivecompensation, when his performance is linked with a blockchain.Similarly, a virtual reality game can be linked with a blockchain forcompensation/locating a suitable affinity group, when the virtualreality game is played.

As an example, the near real-time/real-time wearable bioelectronicssubsystem 1580, as an augmented reality personal assistant can beutilized for (a) augmenting digital information atop the real world(e.g., directions over the street in front of the user) or (b) adding adigital object onto the real world (e.g., a virtual post-itnote/graffiti on a museum wall) or (c) enhancing a real object/realevent with reviews/edits/social recommendations or (d) creating aninstant social graph (personal analytics) of the user with userlocation, user selfie (may also utilize depth sensing technology) anduser instant activities. Such social graphs can be shared with otherusers in real-time/near real-time.

The near real-time/real-time wearable bioelectronics subsystem 1580, asan augmented reality personal assistant can include an active opticalwaveguide device that can estimate eye aberrations of the user andproject an aberration corrected image into the eyes of the user. Such anoptical waveguide device can be (a) decorated with optical nanoantennas(e.g., FIG. 12K) on top of the optical waveguide and/or (b) integratedwith an actively tunable optical material (e.g., a phase change materialGST (Ge₂Sb₂Te₅) or a phase transition material vanadium dioxide.

The near real-time/real-time wearable bioelectronics subsystem 1580, asan augmented reality personal assistant can include a network ofphotonic integrated circuits on silicon nitride thin-film orbenzocyclobutene (BCB) polymer deposited/lifted off on the substrate(e.g., glass) of the display, incorporating display pixels 1020. Thenetwork of photonic integrated circuits includes waveguides, wherein thewaveguides are optically coupled with light (light from quantum dotred/green/blue light emitting diodes or lasers or two-dimensionalmaterial based light sources, as in 12Z2). A section of the photonicintegrated circuit can include about 100 pixels (e.g., an array of tenpixels by ten pixels), wherein each pixel can have an array ofdielectric Mie-type resonators to project an image into the eyes of theuser. For example, 50 titanium dioxide nanopillars (each titaniumdioxide nanopillar is about 250 nanometers in diameter, about 150nanometers apart in center-to-center) can be utilized as dielectricMie-type resonator arrays to project an image into the eyes of the user.However, an electrically activated optically tunable material (e.g.,samarium nickelate (SmNiO₃) or vanadium dioxide) or ferroelectricmaterial (e.g., barium strontium titanate (BST)) can be utilized insteadof titanium dioxide for active control of light propagation/image intothe eyes of the user.

In another embodiment, on top of the substrate (e.g., glass) of thedisplay incorporating display pixels 1020, a network of silicon nitridewaveguides can be fabricated/constructed. The network of silicon nitridewaveguides can route light (e.g., light from quantum dot red/green/bluelight emitting diodes or lasers or two-dimensional material based lightsources, as in 12Z2). Above the silicon nitride waveguides, a layer(about 1 micron in thickness) of an electrically activated opticallytunable material can be fabricated/constructed. On top of theelectrically activated optically tunable material, there aretransparent/niobium electrodes, integrated with tiny openings in theelectrodes to allow light (which is guided via silicon nitridewaveguides) to pass through. Beneath the tiny openings in theelectrodes, the waveguides break into a series of sequential ridges,which can act as diffraction gratings to direct light down through theholes and concentrate the light into a beam narrow enough toward aneye/retina. Alternatively, a hologram/pair of holograms coupled with oneor more waveguides can be utilized to direct the light into a beamnarrow enough toward an eye/retina.

Furthermore, the integration of a surface normal light modulator (e.g.,graphene based surface normal spatial light modulator (SLM)) with thediffraction gratings) can enable the eye to receive light intime-varying intensities.

Additionally, the photonic integrated circuit in silicon nitridethin-film or benzocyclobutene polymer deposited/lifted off on thesubstrate of the display with an array of v-shaped metal resonators anenable holograms over the substrate of display, incorporating displaypixels 1020, when light sources are generally lasers/quantum-dot lasers.

Additionally, a two-dimensional array of Mie-type resonators (e.g.,silicon nanodisks of about 500 nanometers in diameter at about 750nanometers apart-center of one silicon nanodisk to next one) embedded inliquid-crystals on a glass substrate, wherein the glass substrate isintegrated on a transparent semiconductor (e.g., amorphous indiumgallium zinc oxide/IGZO). The upper electrode on liquid-crystals is atransparent electrode (e.g., indium tin oxide). By applying voltage,liquid-crystal molecules orient perpendicular to Mie-resonators—thus,interacting with incoming light beams to enable an electrically tunabledynamic display/hologram, depending on the orientation of liquid-crystalmolecules.

Alternatively, a topological insulator (e.g., Sb₂Te₃)/artificialtopological insulator (e.g., utilizing alternating layers of topologicaland standard insulators) can have a low refractive index on the surfaceand an ultra-high refractive index in bulk. A thin-film/stretchable film(e.g., poly(dimethylsiloxane) film) of the topologicalinsulator/artificial topological insulator can modulate the phase oflight (from a fast-direct laser writing (DLW) system) to givethree-dimensional depth, as in holograms. It should be noted that astretchable film can also switch between images.

Furthermore, the photonic integrated circuit in silicon nitridethin-film or benzocyclobutene polymer deposited/lifted off on thesubstrate of the display with an array of dielectric/semiconductor(e.g., AiGaAs) metamaterial Mie-type resonators (about 500 nanometers indiameter, 200 nanometers in depth and 3 to 5 microns in pitch) can beutilized to convert infrared light to visible light, directly in line ofsight.

Additionally, it should be noted that all components/devices and/orapplication examples and/or embodiments of the portable internetappliance 1600 can be utilized with the near real-time/real-timewearable bioelectronics subsystem 1580, as an augmented reality personalassistant.

It should be apparent that one or more features of the portable internetappliance 1600 (as discussed later) can be combined with one or morefeatures of the near real-time/real-time wearable bioelectronicssubsystem 1580.

In particular, the near real-time/real-time wearable bioelectronicssubsystem 1580, as an augmented reality personal assistant can beintegrated/co-packaged with (a) system-on-chip/learning neural processor(either electrical or photonic), (b) interconnection within thesystem-on-chip, (c) Terahertz band transceiver, (d)tunable/graphene/metamaterial based antenna, (e) software-defined radio,(f) 360-degrees spherical camera, (g) ultrathin/lensless/multi-spectralband camera, (h) sensor integrated with multi-spectral band camera, (i)three-dimensional video conferencing subsystem, (j) embeddedconfiguration of projector, camera & sensor, (k) embedded configurationof projector, camera, sensor & microprocessor/system-on-chip, (l)embedded configuration of display, camera, sensor &microprocessor/system-on-chip, (m) sensor-system-on-chip, (n) personalawareness assistant module, (o) solar cell, (p) wireless charging, (q)ultrathin display and (r) ultrathin battery, as described below inconnection with the portable internet appliance 1600.

Portable Internet Appliance

Details of the portable internet appliance 1600 have beendescribed/disclosed in U.S. Non-Provisional patent application Ser. No.12/238,286 entitled, “PORTABLE INTERNET APPLIANCE”, filed on Sep. 25,2008; “SYSTEM & METHOD FOR MACHINE LEARNING BASED USER APPLICATION”,filed on Apr. 16, 2012 and “SYSTEM AND METHOD OF AMBIENT/PERVASIVEUSER/HEALTHCARE EXPERIENCE”, filed on Jun. 1, 2016 and the entirecontents of this US Non-Provisional Patent Application are incorporatedherein.

The portable internet appliance 1600 is about 125 millimeters long, 75millimeters wide and 20 millimeters thick. It has a microprocessor(e.g., Intel's x86 based Medfield or Qualcomm's ARM based Snapdragon 800or Nvidia Tegra) and a system operating algorithm (stored in a datastorage component of the portable internet appliance 1600) which can beelectrically connected/coupled/interacted with: (a) a memory component,(b) a data storage component, (c) an IP address stored in the memorycomponent, (d) an internet security algorithm (internetfirewall/spyware/user-specified security control and authentication),(e) a touch/multi-touch sensitive foldable/stretchable/split/wrap-arounddisplay, wherein at least one section of the display is integrated witha component such as PCS 1280/DCS 1285 and alternatively, atouch/multi-touch sensitive stretchable/split/wrap-around display,wherein at least the back side of the display is integrated with a solarcell component to collect residual back reflected light, (f) two (2)high definition (HD) (e.g., one giga pixel) multi-spectral bandvisible/near-infrared/infrared/three-dimensional image capturing cameras(two (2) cameras-one camera for video chat and another camera forphotography, however, a 180-degrees angle rotating camera is alsosuitable), (g) a video conferencing system-on-chip (integrated with adynamic video compression module—the video compression module could beeither an electronic module and/or an algorithm), (h) a surround soundcomponent (e.g., a micro-electrical-mechanical-systems based siliconmicrophone component Analog ADMP 401 or an equivalent component fromakustica), (i) a personal area network (PAN) wireless transceiver module(e.g., Wibree/Bluetooth/Wi-Fi/ultra-wideband/millimeter wave (including60 GHz)/terahertz band with antenna(s) or a software-defined radio witha tunable antenna), (j) near-field communication to enable thefollowing: product/service discovery/initiation, peer-to-peerexchange/transfer/share/transaction, machine-to-machineexchange/transfer/share/transaction, remote access of a system/terminaland access authentication, (k) DASH 7 wireless transceiver (DASH 7 is aninexpensive instant-on, long range, low power P2P wirelesscommunications standard for applications requiring modest bandwidth liketext messages, sensor readings, or source and operates on a single,global frequency 433 MHz. Unlike Wi-Fi, DASH 7 operates at a radiofrequency which provides for both long range (up to 1 Km) and excellentindoor signal propagation. Dash 7 is a complement to near-fieldcommunication, driven by a combination of sensing function with wirelesstransmission), (l) a location measurement component (e.g., an electroniccompass/indoor positioning system/global positioning system withantenna(s)), (m) a radio frequencyidentification/one-dimensional/two-dimensional barcode/quick responsecodes reader, (n) a communication wireless transceiver module (e.g.,WiMax/LTE) with antenna(s)/metamaterial antenna(s) or a software-definedradio with a tunable antenna/tunable metamaterial antenna), (o) a sensorbased communication component (e.g., low-power radio frequencyidentification presence tag that can announce a user's identity andlocation or can communicate to turn on the temperature of a home or cantext the user's wife what things she might need from the grocery storeon the way back from the user's office or can text the nearest Starbucksfor the user's favorite coffee, as the user's car approaches the nearestStarbucks or the nearest Starbucks can text an electronic coupon to theuser for purchasing the user's favorite coffee, as the user/user's carapproaches the nearest Starbucks), (p) a biometric component (e.g.,finger print/retina scan sensor), (q) a time-shift module (e.g., theuser's favorite live basketball game can be recorded to be watched at alater time), (r) a place-shift module (e.g., the user's favorite livebasketball game is configured to be watched anywhere, irrespective ofthe user's location), (s) a personal awareness assistant module, (t) afirst algorithm for content (voice, video and data)—over-IP—thus thefirst algorithm for content over-IP via an ambient Wi-Fi/WiMax network,can disrupt a traditional carrier controlled cellular business model,(u) a second algorithm of a voice-to-text-to-voice conversion algorithm,(v) a third algorithm including one or more of the following: a voicerecognition/editing algorithm, a hand-writing recognition algorithm, animage authentication algorithm, a facial recognition algorithm and abiometric recognition algorithm (e.g., a heartbeat/voice signature canvalidate the user depositing an image of a check/banknote via digitalbanking), (w) a fourth algorithm for rendering intelligence (e.g.,artificial intelligence (including self-learning artificialintelligence), computer vision (including self-learning computervision), data mining, fuzzy/neuro-fuzzy logic, machine vision (includingself-learning machine vision), natural language processing, neuralnetworks (including self-learning neural networks), pattern recognition,reasoning modeling and self-learning (including evidence basedself-learning)), (x) a fifth algorithm for evidence based learning,hypothesis generation and natural language processing, (y) a sixthalgorithm for a voice activated search engine configured by naturallanguage processing, as a digital personal assistant, (z) a seventhalgorithm including one or more of the following:algorithm-as-a-service, behavior modeling (e.g., if the user prefers towatch basketball games-such behavior patterns can be analyzedstatistically with a predictive modeling algorithm for sending abasketball ticket related coupon to the user), physical search algorithm(e.g., the portable internet appliance 1600 can scan/tag a productphysically/directly to search-product manufacturer, product price,product availability, product reviews and store locations/distributioncentres of the product) and a semi-autonomous or autonomous softwareagent (e.g., a semi-autonomous or autonomous software agent can searchthe internet with/without the user's input to find any usefulinformation for the user or for the preferences/behavior patterns of theuser)—it should be noted that the semi-autonomous or autonomous softwareagent can be algorithmically coupled/integrated with the sixth algorithmfor voice activated search engine (aa) an electrical powering component(e.g., a battery), (ab) a solar cell component, (ac) a supercapacitor(e.g., a graphene based supercapacitor) to store electrical power, (ad)a lab-on-chip/biosensor, (ae) an ionized gas cloud based coolingcomponent for the microprocessor/system-on-chip and (af) afixed/reconfigurable outer case/package, wherein the portable internetappliance 1600 can morph into a smaller form factor (e.g., a size of amulti-purpose programmable smart card/wristwatch-style device).

System-On-Chip of Portable Internet Appliance

A first system-on-chip integrates: (a) a digital microprocessor based onplanar transistors/three-dimensional transistors/spin-transistors; (b)memory; (c) a graphic processor; and (d) chip-to-chip opticalinterconnect. Details of an optical interconnect have beendescribed/disclosed in U.S. Non-Provisional patent application Ser. No.13/448,378 entitled “SYSTEM & METHOD FOR MACHINE LEARNING BASED USERAPPLICATION”, filed on Apr. 16, 2012 and the entire contents of this USNon-Provisional Patent Application are incorporated herein.

Additionally, the digital microprocessor in the first system-on-chip canintegrate a VLSI Electronic IC with memristors elements (e.g.,silver/amorphous-silicon/poly-silicon structure) for neural likeprocessing based on electrical inputs (e.g., current/voltage). This canbe referred as an electrical neural learning processor.

Additionally, the digital microprocessor in the first system-on-chip canintegrate a VLSI Photonic IC (a photonic flip-flop based on twomulti-wavelength ring lasers coupled with one SOA or plasmonic laserswith a metallic cavity) for ultrafast information processing.

Both the VLSI Photonic IC (VLSI-PIC) and VLSI Electronic IC (VLSI-EIC)can be fabricated/constructed by co-integration epitaxy of III-Vmaterial on silicon.

A second system-on-chip integrates the first system-on-chip and anembedded internet firewall.

A third system-on-chip integrates the second system-on-chip and anembedded spyware.

A fourth system-on-chip integrates the third system-on-chip and auser-specific security control/authentication.

A fifth system-on-chip integrates the fourth system-on-chip and apersonal area network wireless component (e.g.,Wibree/Bluetooth/near-fieldcommunication/Wi-Fi/ultra-wideband/millimeter wave (including 60GHz)/terahertz band).

Additionally, a sixth system-on-chip can integrate the fifthsystem-on-chip and a photonic neural learning processor, wherein thephotonic neural learning processor (can be useful for machine learningand/or image/pattern recognition and/or Big Data analysis) can befabricated/constructed for example, utilizing a cascaded configurationof interferometers (e.g., Mach-Zehnder type interferometers), 3-dbcouplers and waveguide based phase shifters. Heat applied to thewaveguide base phase shifter(s) can direct light beams to change itsshape. It should be noted that interferometer(s) and/or waveguide basedphase shifter(s) can be fabricated/constructed, utilizing a phasechange/phase transition material for faster response to an externalstimulus (e.g., heat or voltage) and/or integrated with saturableabsorbers (e.g., graphene integrated saturable absorber). To reducethermal cross-talk between the heating elements, thermal isolationtrenches can be fabricated/constructed between the heating elements. Itshould be noted that the photonic neural processor can be a standalonesubsystem. Furthermore, various embodiments of system-on-chips/neuralnetworks based system-on-chips have been described/disclosed describedin U.S. Non-Provisional patent application Ser. No. 14/999,601 entitled“SYSTEM AND METHOD OF AMBIENT/PERVASIVE USER/HEALTHCARE EXPERIENCE”,filed on Jun. 1, 2016 and the entire contents of this US Non-ProvisionalPatent Application are incorporated herein. Such a system-on-chip/neuralnetworks based system-on-chip can replace themicroprocessor/super-processor and enable cognitive/neural likecomputing.

Interconnection within a System-On-Chip of Portable Internet Appliance

Connecting circuits (chip-to-chip) within a system-on-chip can beachieved by an optical interconnect. Details of an optical interconnecthave been described/disclosed in U.S. Non-Provisional patent applicationSer. No. 13/448,378 entitled “SYSTEM & METHOD FOR MACHINE LEARNING BASEDUSER APPLICATION”, filed on Apr. 16, 2012 and entire contents of this USNon-Provisional Patent Application are incorporated herein.

As illustrated in FIG. 17D, stacking of circuits within a system-on-chipcan be realized, by utilizing an array of vertical nanotubes (e.g.,boron nitride/multi-walled carbon nanotubes) and a horizontal frame of atwo-dimensional material (e.g. graphene/molybdenum disulphide) orsilicone—thus substantially eliminating interconnected wires.

Terahertz Band Transceiver of Portable Internet Appliance

It should be noted that a terahertz band transceiver can be based onsilicon-germanium heterojunction bipolar transistors (HBTs) or a hybridsilicon-germanium and gallium nitride based device enhanced withgraphene.

Tunable Antenna & Software-Defined Radio of Portable Internet Appliance

A tunable radio-frequency carbon nanotube cavity can tune in between 2GHz and 3 GHz. By merging many antennas, utilizing a tunable carbonnanotube cavity and an analog/digital converter, a software-definedradio can be fabricated/constructed.

Graphene or Metamaterial Based Antenna of Portable Internet Appliance

A graphene based antenna can enable faster wireless connection. Graphenebased antennas can be fabricated/constructed, utilizing an array ofstrips of graphene material (about 10 to 100 nanometers width and 1micron in length). Transmission and reception at a terahertz band canoccur at these dimensions. Electromagnetic waves in the terahertz bandcan interact with plasmonic waves of electrons at the surface of thearray of strips of graphene material to send and/or receive data.

360-Degrees Angle Spherical Camera of Portable Internet Appliance

A spherical 360-degrees angle image can be generated by shooting imagesin four directions (left, right, up and down) centering on a sphericalcamera with two super-wide-angle lenses at once. Incident light from thesuper-wide-angle lenses are reflected by a prism mirror (at 90-degreesangle with respect to each other) and received by two image sensors. Twoimages obtained with two image sensors are thus synthesized to generatea complete spherical image.

Lensless Camera of Portable Internet Appliance

A lensless camera has: (a) an array of liquid-crystal devices thatallows light to pass through, (b) a red-green-blue photoelectric sensorand (c) a microprocessor to control the array of liquid-crystal devicesand to process the data that is received from red-green-bluephotoelectric sensor. To create an image, the array of liquid-crystaldevices is placed between an item (to be imaged) and the single pixelsensor. The microprocessor sends signals to the array of liquid-crystaldevices causing a few liquid-crystals in the array of liquid-crystaldevices to allow light to pass through, each serves as a tiny opticalaperture. The liquid-crystals in the array of liquid-crystal devices canbe chosen by a random number generator and the end result is just aspeckled pattern. The photoelectric sensor can capture the light that isallowed to pass through the liquid-crystals in the array ofliquid-crystal devices and send the data to the microprocessor. Tocreate a single picture, multiple image-captures can be taken withdifferent random patterns generated on the array of liquid-crystaldevices. The data from all of the image-captures can be processed at themicroprocessor afterwards and the result is a single photograph. Themore image-captures are taken, the higher is the resolution of the finalimage.

In another embodiment, a lensless camera can be fabricated/constructed,utilizing the principle of an insect's compound eye/light field opticswith over 200 photodiodes, wherein each photodiode is placed just belowa microlens, wherein each microlens is configured to capture 40 by 40pixels. The resulting image can be electronically focused/processed intoa three-dimensional image afterwards.

Three-Dimensional Video Conferencing of Portable Internet Appliance

An array of (at least four) front-facing cameras can provide stereoviews and motion parallax (apparent difference in a direction ofmovement produced relative to its environment). Each camera can create alow dynamic range depth map. However, an array of cameras can create ahigh dynamic range depth map. Thus, the portable internet appliance 1600can enable three-dimensional video conferencing.

Multi-Spectral Band Camera of Portable Internet Appliance

Nano-scaled lithography (e.g., phase mask/electron beam lithography) andreactive ion/plasma etching of two gold electrodes can be utilized toelectrically contact on graphene.

Graphene can be chemically functionalized with an array of quantumdots/nanocrystals. Quantum dots/nanocrystals can be arranged accordingto their size and the specific wavelength of the spectrum to beabsorbed.

Silicon (Si) quantum dots/nanocrystals can be tuned in visiblewavelength range. Lead-sulphide (PbS) quantum dots/nanocrystals can betuned in short-wavelength infrared (SWIR) and near-infrared (NIR)ranges.

The above graphene device chemically functionalized with quantumdots/nanocrystals can act like a transistor and the carrier density inthe graphene can be changed by varying the gate voltage.

Graphene functionalized with an array of quantum dots/nanocrystals canact as a multi-spectral band (visible/near-infrared/infrared)photodetector/camera pixel.

In another embodiment, graphene quantum dots can trap light-generatedelectron particles for a much longer time, resulting in a much strongerelectric signal to be processed into an image. Furthermore, graphenequantum dots themselves can be utilized to fabricate/construct amulti-spectral band camera. Fabrication of graphene quantum dots can beas follows: a monolayer graphene can be mechanically exfoliated on anultrathin silicon dioxide/silicon substrate. The graphene photodetectorcan be fabricated/constructed (by photolithography and lift-off process)into a field effect transistor structure with a source metal electrode,a drain metal electrode and a gate terminal (the gate terminal is at thebottom of the silicon substrate). A nano-scaled sacrificial metal can bedeposited on the graphene by electron beam evaporation and then thenano-scaled sacrificial metal can be wet etched to form graphene quantumdots of various sizes on the ultrathin silicon substrate.

Sensor Integrated with Multi-Spectral Band Camera of Portable InternetAppliance

A multi-spectral band (visible/near-infrared/infrared) camera can beintegrated with a sensor. The sensor can track what the user touches orsees. The sensor can capture the user's voice for spoken commands withthe microphone (of the personal awareness assistant module of theportable internet appliance 1600).

Embedded Configuration of Projector, Camera & Sensor of PortableInternet Appliance

The portable internet appliance 1600 can be integrated with a projector,a camera and a sensor/an array of sensors (e.g., an array oftouch-sensitive sensors) in an embedded configuration (of a projector, acamera and a sensor/an array of sensors) for blurring between reality,virtual reality and augmented reality for an enhanced mixed realityexperience. If a user can enlarge a portion of an image by gentlytouching the screen to enlarge, the projected image will make the sameresponse.

A rear projector can be based on Texas Instrument's Digital LightProcessor projector chip. A typical Texas Instrument's Digital LightProcessor projector chip contains up to 8 million micromirrors. Eachmicromirror can be tilted at a rate of 10,000 times per second toreflect light to create a precise digital image on a surface.

Instead of Texas Instrument's Digital Light Processor projector chip, arear projector can be fabricated/constructed, utilizing a tiltablesingle crystal mirror (of about 1 millimeter in diameter) or amicroelectro-mechanical-system based scanning mirror. The tiltablesingle crystal mirror or a microelectro-mechanical-system based scanningmirror deflects a color (blue, green and red) of light beam from amicroelectro-mechanical-system enabled wavelength tunable surfaceemitting vertical cavity laser, by rapidly switching the angle oforientation—thus building pixel by pixel.

Furthermore, a rear projector can be fabricated/constructed, utilizingthe principle of an insect's compound eye/light field optics withhundreds of light emitting diodes, wherein each light emitting diode isplaced just below a microlens.

A PCS component 1280 is an embedded integration of a projector, a cameraand an emotion sensor/eye motion/gesture/touch sensor (e.g., an emotionsensor can be fabricated/constructing, utilizing analysis of facialexpressions by an algorithm(s) and a camera/infrared camera viewing theuser's facer and a touch sensor can be fabricated/constructed, utilizinga large array of zinc oxide nanowire based transistors).

FIG. 18A illustrates a display configuration with a horizontal spacesharing and vertical three-dimensional stacking of PCS component1280/1285-A and a DCS component 1285/1285-A of the portable internetappliance 1600.

Furthermore, in some cases, it may be suitable to replace the projectorof the PCS component 1280 with a display pixel. A DCS component 1285 isan embedded integration of a display, a camera and an emotion sensor/eyemotion/gesture/touch sensor. Optionally, such an embedded integrationcan be limited to an array of display pixels.

The integrated PCS component 1280 or integrated DCS 1285 can display,record visual information and sense without an external video capturedevice, while the user is sitting in front of it.

Embedded Configuration of Projector, Camera, Sensor &Microprocessor/System-On-Chip of Portable Internet Appliance

The PCS component 1280-A is an embedded integration of a projector, acamera and an emotion sensor/eye motion/gesture/touch sensor and amicroprocessor or first/second/third/fourth/fifth system-on-chip.

Embedded Configuration of Display, Camera, Sensor &Microprocessor/System-On-Chip of Portable Internet Appliance

The DCS 1285-A is an embedded integration of a display, a camera and anemotion sensor/eye motion/gesture/touch sensor and a microprocessor orthe first/second/third/fourth/fifth system-on-chip.

The display itself can have embedded integration of an array of sensors,such sensors can be fabricated/constructed (e.g., optically sensingwaveguides) by a femtosecond laser. Utilizing a femtosecond lasermodule, a two-dimensional/three-dimensional optically sensingwaveguide(s) can be fabricated/constructed at various depths of thedisplay substrate.

The display itself can have embedded integration of (a) a transparentimage sensor based on graphene, (b) a transparent microprocessor basedon nanowires (e.g., zinc oxide nanowires) and (c) a transparent battery.

The display itself can have embedded integration of a transparent solarcell (e.g., CH₃NH₃PbI₃-xClx perovskite based solar cell, utilizingindium tin oxide (ITO) or fluorine-doped tin oxide (FTO) and gold orgraphene electrodes).

Furthermore, the above transparent solar cell can be integrated withvanadium dioxide thin-film/nanoparticles for both electricity generationand electricity saving.

Additionally, the transparent microprocessor can have embeddedintegration of an array of transparent sensors (e.g., transparentvanadium dioxide sensors). Such transparent sensors integrated with thetransparent microprocessor can sense, manipulate and respond quickly,because either feedback or feed forward control is integrated within oneintegrated system-on-chip.

Furthermore, the display itself can be integrated with a vanadiumdioxide thin-film thermochromic device, when it is activated by eithervoltage or temperature.

The integrated PCS component 1280-A or integrated DCS 1285-A candisplay, record visual information, sense and process data/informationwithout an external video capture device, while the user sits in frontof it.

Split Display/Wrap-Around/Foldable-Stretchable Display/Dual Displays OfPortable Internet Appliance

The portable internet appliance 1600 can have a split display, whereinone section of the display is a high pixel density-high brightnessliquid-crystal display/organic light emitting display and wherein theother section of the display is based on a component, such as PCS1280/DCS 1285.

Alternatively, the portable internet appliance 1600 can have awrap-around display or dual displays, wherein one display is a highpixel density-high brightness liquid-crystal display/organic lightemitting display and wherein another display is integrated with acomponent such as PCS 1280/DCS 1285.

The display can be reconfigured for at least two (2) different sizes,utilizing a foldable/stretchable display, which can befabricated/constructed, utilizing a graphene sheet and/or an organiclight-emitting diode (OLED) connecting/coupling/interacting with aprinted organic transistor or carbon nanotube based thin-film transistorand a rubbery conductor (e.g., a mixture of a carbon nanotube/goldconductor and a rubbery polymer) with a touch/multi-touch sensor.

Furthermore, a foldable/stretchable display can befabricated/constructed, utilizing an array of flexible polymerwaveguides/multi-mode plastic fibers, wherein the input of each flexiblepolymer waveguide/multi-mode plastic fiber can be integrated with a highbrightness light source and the output of the above flexible polymerwaveguide/multi-mode plastic fiber can be integrated with a highbrightness white phosphor thin-film and a dense matrix of blue, greenand red thin-film filters or tunable thin-film filters.

Various spatial arrangements of the flexible polymerwaveguide/multi-mode plastic fiber, high brightness light source, highbrightness white phosphor thin-film and thin-film filters/tunablethin-film filters are possible.

Touch Sensitive Interactive Three-Dimensional Liquid-Crystal Display ofPortable Internet Appliance

The display of the portable internet appliance 1600 can be athin-film-transistor liquid-crystal three-dimensional liquid-crystaldisplay. A thin-film-transistor liquid-crystal display is anactive-matrix liquid-crystal display, a special variant of aliquid-crystal display that utilizes thin-film transistor technology toimprove image qualities (e.g., contrast and addressability). Thin-filmtransistors are tiny switching thin-film transistors/capacitors-arrangedin a matrix on a glass substrate. To address a particular pixel, theproper row is switched on and then a charge is sent down to the propercolumn. Since all of the other rows that the column intersects areturned off, only the capacitor at the designated display pixel receivesthe specified charge. The capacitor is able to hold the specified chargeuntil the next refresh cycle. With the controlled amount of voltagesupplied to a liquid-crystal, the liquid-crystal can untwist only enoughto allow some light to pass through.

Instead of a liquid-crystal material, a polymer stabilizedliquid-crystal/photoreactive polymer stabilized liquid-crystal materialcan be utilized.

Additionally, utilizing plasma enhanced chemical vapor deposition(PECVD) and electron beam lithography, an array of vertical nanotubes(e.g., multi-walled carbon nanotubes at about 2 to 5 microns apart) canbe fabricated/constructed on a glass substrate. The array of verticalnanotubes can act as an array of vertical microlens-electrodes ofvariable focal lengths, controlled by an applied voltage. Furthermore,the array of vertical nanotubes, as an array of verticalmicrolens-electrodes of variable focal lengths can be switched on or offby an applied voltage.

Alternatively, an array of vertical nanowires (e.g., zinc oxidenanowires) can be utilized instead of an array of vertical nanotubes.Additionally, an array of vertical nanowires can befabricated/constructed by spin-on-nanoprinting method.

Currently, due to larger pixel size, the field of view of thethree-dimensional liquid-crystal display is limited. Verticalnanotubes/nanowires based three-dimensional liquid-crystal displayincorporating of millions of nano-scaled pixels can producethree-dimensional liquid-crystal display with a wider field view.

Additionally, these nano-scaled pixels can be tuned by integrating withmillions of micromirrors, wherein each micromirror can be activated by amicroelectro-mechanical-system actuator (e.g., Texas Instrument'sDigital Light Processor projector chip).

A polymer stabilized liquid-crystal/photoreactive polymer stabilizedliquid-crystal material integrated with an array of verticalnanotubes/nanowires can enable a three-dimensional liquid-crystaldisplay, where a hologram can be changed dynamically in real-time.

Furthermore, a polymer stabilized liquid-crystal/photoreactive polymerstabilized liquid-crystal material integrated with (a) an array ofvertical nanotubes/nanowires and (b) an array of micromirrors (whereineach micromirror is activated by a microelectro-mechanical-systemactuator) can enable a three-dimensional tunable liquid-crystal display,where a hologram can be changed dynamically in real-time.

Furthermore, the above three-dimensional liquid-crystal display can betouch/multi-touch sensitive.

The above touch/multi-touch sensitive three-dimensional liquid-crystaldisplay can be a foldable/stretchable/split/wrap-around display.

The above touch/multi-touch sensitive three-dimensional liquid-crystaldisplay can be an interactive display.

Sensor-System-On-Chip (S-SoC) of Portable Internet Appliance

The portable internet appliance 1600 can be integrated with asensor-system-on-chip. The sensor-system-on-chip integrates (a) asensor/an array of sensors, (b) microcontroller/microprocessor and (c) alow-power radio. The sensor/array of sensors can be aware, always on,intelligent, intuitive (e.g., utilizing fuzzy logic based instructions)and wirelessly connected with other sensors. Furthermore, thesensor-system-on-chip can be embedded with the portable internetappliance.

Personal Awareness Assistant Module of Portable Internet Appliance

The personal awareness assistant module can include: a secondmicroprocessor component, a second memory component, a microphonecomponent and a scrolling audio recording buffer component. Furthermore,the personal awareness assistant module can also include: a second datastorage component and a second camera component.

The personal awareness assistant module can be always on. It canpassively listen to what the user says in a natural language and canrespond to particular contexts and situations. For example, the user canhear about a product on the radio and then the user can create areminder by speaking to the personal awareness assistant module. Theportable internet appliance 1600 can then enable further purchasing ofthe product at a later time.

For example, when the user is introduced to a person, the personalawareness assistant module can automatically recognize the person andmay take a low-resolution photo. Once the personal awareness assistantmodule collects the information, it can automatically categorize theinformation into a pre-designated database with audio, digital image,time/date stamp and indoor positioning/outdoor positioning location.Because the data is stored contextually, information retrieval can bestraightforward. A simple voice command inquiry, such as whom did I meeton Apr. 15, 2009 at 12 p.m.?, enables the personal awareness assistantmodule to bring up the appropriate information about that specificperson. Thus, the portable internet appliance 1600 (integrated with thepersonal awareness assistant module) is context-aware.

Furthermore, the voice recognition/editing algorithm can enhance thecapability of the personal awareness assistant module. Additionally, aface/emotion recognition algorithm can enhance the capability of thepersonal awareness assistant module.

Solar Cell Component of Portable Internet Appliance

The solar cell can be a quantum dot-nanowire-plasmon solar cell/an arrayof microscopic solar cells integrated with an array of refractivemicrolenses.

By way of an example and not by way of any limitation, typicalphotovoltaic material can be copper indium galliumdiselenide/CdS/CdTe/graphene/organic material/crystallinesilicon/polycrystalline silicon. Furthermore, monolithically integratedlattice matched, bangdgap-optimized and current matched multi junctionsof III-V semiconductor materials can be used, wherein each junctioncontaining a p-n junction and tuned to a particular spectrum of light,reducing losses and thereby increasing efficiency.

An organic material with squaraine dye coating is based on the principleof Förster resonance energy transfer (FRET) mechanism, wherein extraenergy can migrate from one molecule to another molecule over arelatively longer distance. Squaraine dye broadens the spectralabsorption of the sunlight.

In singlet-exciton fission, an arriving photon from the sunlight cangenerate two (2) excitons (excited states) yielding two (2) electrons.Pentacene generates two (2) excitons (excited states) yielding two (2)electrons in a narrow visible spectrum of the sunlight. However,pentacene (an organic dye) and/or other materials for singlet-excitonfission in another spectrum of the sunlight can be integrated viacoating or wafer stacking/bonding (wafer stacking/bonding is useful,when the material is not suitable for coating) for enhanced electrongeneration.

The top surface or back surface of the photovoltaic material (e.g.,copper indium gallium diselenide/CdS/CdTe/graphene/organicmaterial/crystalline silicon/polycrystalline silicon/monolithicallyintegrated multi junctions of III-V semiconductor materials) can beintegrated with a singlet-exciton fission material or an array ofsinglet-exciton fission materials, depending on the configuration of thesolar cell component.

Furthermore, photovoltaic material can be integrated (e.g., doped) witha light sensitive compound/protein.

Furthermore, photovoltaic material can be integrated with a lighttrapping structure or an optical metamaterial based light trappingstructure for light collection from many incident angles. The lighttrapping structure or an optical metamaterial based light trappingstructure can be deposited directly onto the photovoltaic material.Alternatively, the light trapping structure or an optical metamaterialbased light trapping structure can be deposited on a suitable substrateand stacked/bonded (e.g., Soitec company's smart stacking layer transfertechnology for processed wafers).

Unlike conventional solar cells, electrical contacts can run below thelight trapping structure.

Graphene based photovoltaic material can be fabricated/constructed asfollows: an ultrathin graphene sheet can be fabricated/constructed, bydepositing carbon atoms in the form of graphene on nickel (thin-filmsubstrate) from methane gas.

Additionally, transition metal dichalcogenides (TMDC) or aerographite (asynthetic foam consisting of a porous interconnected network of tubularcarbon) monolayers can be sandwiched between/within two layers ofgraphene. Transition metal dichalcogenides or aerographite monolayerscan act as very efficient light absorbers.

Furthermore, an array of vertical/vertically ordered plasmonicnanostructures of metal can be directly fabricated/constructed on thetop surface of graphene. The plasmonic nanostructures of metal canenhance local electromagnetic fields in graphene by coupling incominglight with electrons on the surface of the metal.

Furthermore, instead of an array of vertical/vertically orderedplasmonic nanostructures of metal, nanowires of indium gallium arsenide(InGaAs) can be grown on the top surface of graphene by van der Waalsepitaxy induced phase segregation.

Alternative to an array of vertical/vertically ordered nanowiresintegrated on the top surface of the photovoltaic material, the topsurface of the photovoltaic material can have an array of verticalnanowires (e.g., zinc oxide nanowires) to concentrate rays of sunlightinto a very small area of each nanowire by a factor of about ten (10) ata given wavelength of the sunlight. Because the diameter of a verticalnanowire is smaller than the wavelength of sunlight, it can causeresonances in the intensity of the sunlight in and around nanowires toproduce concentrated sunlight, at a much higher conversion efficiency ofthe sunlight.

Furthermore, the top surface of the array of vertical/vertically orderednanowires or vertical nanowires can be integrated with an array ofcolloidal deposited/self-assembled variable sized quantum dots. Thesevariable sized quantum dots can absorb the sunlight over a much widerrange of wavelengths. These variable sized quantum dots can be arrangedaccording to their size and according to the specific wavelength of thesolar spectrum that is absorbed. Thus, the harvesting of the sunlight'spower (absorption) is increased.

Furthermore, instead of colloidal deposited/self-assembled variablesized quantum dots, an ultra thin-film of silicon nanoparticles (1 to 3nanometers) can be deposited, forming a transparent layer of siliconnanoparticles. Large voltage enhancement with a dramatic increase inpower ranging from as much as 60-70% in the ultraviolet-blue (UV)spectrum using these silicon nanoparticles and a significant boost inpower by as much as 10% in the visible light spectrum can be obtained.

Instead of an array of plasmonic nanostructures of metal, an array ofmetamaterial structures of multi-layered metal-dielectric thin-film canbe directly fabricated/constructed on the top surface of graphene.

A protective film can be deposited over the graphene and nickel(thin-film substrate on which graphene was grown) and dissolved in asuitable acid.

The unprotected back surface of graphene can be suitably coated withpentacene and then it can be attached to a flexible polymer sheet.Instead of a single layer, several layers of graphene (wherein eachlayer of graphene is protected on a flexible polymer sheets) can act asan efficient graphene photovoltaic material.

Furthermore, an array of plasmonic optical nanoantennas at the substrate(of the quantum dot-nanowire-plasmon solar cell) can befabricated/constructed to enhance both light trapping and spectralefficiency.

Furthermore, sunlight can be collected by a micro-reflector and directedat a very specific angle into an array of thin-film optical filters (ornano-scaled optical filters), wherein each thin-film optical filter (oreach nano-scaled optical filter) is configured to transmit a spectralband/slice of sunlight spectrum to illuminate a spectrum-matchingquantum dot-nanowire-plasmon solar cell (out of an array of quantumdot-nanowire-plasmon solar cells).

Each quantum dot-nanowire-plasmon solar cell is fabricated/constructed,utilizing a different photovoltaic material, wherein each photovoltaicmaterial is coated with pentacene. Such a configuration of an array ofquantum dot-nanowire-plasmon solar cells of different photovoltaicmaterials coated with pentacene coating can significantly increaseefficiency of the solar cell.

An alternative embodiment of the solar cell, a three-dimensional solarcell can be fabricated/constructed, by depositing a photovoltaicmaterial: CdS/CdTe/polycrystalline silicon or alternatively,roll-to-roll processing of a photovoltaic material: (e.g.,graphene/organic material) on an array of vertical cubes.

Each vertical cube can consist of a large array of nanotubes (e.g.,carbon nanotubes). The nanotubes are grown on a bottom metal pattern(the bottom metal film is deposited, photolithographically patterned andreactive ion-plasma etched on a substrate).

By way of an example and not by way of any limitation, a photovoltaicmaterial such as polycrystalline silicon can be deposited on the arrayof cubes. Then pentacene can be deposited on the top surface of thepolycrystalline silicon.

The top surface of the photovoltaic material can have an array ofvertical nanowires (e.g., zinc oxide nanowires) to concentrate rays ofsunlight into a very small area of each nanowire by a factor of aboutten (10) at a given wavelength of the sunlight. Because the diameter ofa vertical nanowire is smaller than the wavelength of sunlight, it cancause resonances in the intensity of the sunlight in and aroundnanowires to produce concentrated sunlight, at a much higher conversionefficiency of the sunlight.

Furthermore, the top surface of the array of vertical nanowires can beintegrated with an array of colloidal deposited/self-assembled variablesized quantum dots. These variable sized quantum dots can absorb thesunlight over a much wider range of wavelengths. These variable sizedquantum dots can be arranged according to their size and according tothe specific wavelength of the solar spectrum that is absorbed. Thus,the harvesting of the sunlight's power (absorption) is increased.

Furthermore, instead of colloidal deposited/self-assembled variablesized quantum dots, an ultra thin-film of silicon nanoparticles (1-3nanometers) can be deposited, forming a transparent layer of siliconnanoparticles. Large voltage enhancement with a dramatic increase inpower ranging from as much as 60-70% in the ultraviolet-blue spectrumusing these silicon nanoparticles and a significant boost in power by asmuch as 10% in the visible light spectrum can be obtained.

Furthermore optionally, an array of plasmonic optical nanoantennas atthe substrate can be fabricated/constructed to enhance both lighttrapping and spectral efficiency of the three-dimensional solar cell.

The photovoltaic material on the array of cubes is then encapsulatedwith a transparent top electrode (e.g., indium tin oxide/graphene)—thusforming the three-dimensional solar cell.

Furthermore, the three-dimensional solar cell can be a microscopic solarcell. The microscopic solar cell is about 0.25 millimeters to 1millimeter in diameter and about 10 times thinner than the conventionalsolar cell.

Other Design Considerations of Portable Internet Appliance

The portable internet appliance 1600 can be dramatically thinner, byutilizing (a) a metamaterial based camera, (b) an ultrathin display and(c) an ultrathin battery Ultrathin Camera Of Portable Internet Appliance

An ultrathin camera based on metamaterial can enable light to passthrough a two-dimensional array of gold metamaterial elements. Thetwo-dimensional array of gold metamaterial elements can befabricated/constructed, utilizing electron beam lithography on a 60nanometers thick silicon wafer.

Ultrathin Display of Portable Internet Appliance

An ultrathin photonic crystal display can be constructed by opticallypumping different sized photonic crystals, wherein each photonic crystalcan emit blue or green or red light based on a photonic crystal'sinherent diameter. An optical pump can be generated (from an opticalemission) by electrical activation of semiconductor quantum-wells. Blue,green and red light can be multiplexed to generate white light. Detailsof such a quantum dot based display have been described/disclosed inDYNAMIC INTELLIGENT BIDIRECTIONAL OPTICAL ACCESS COMMUNICATION SYSTEMWITH OBJECT/INTELLIGENT APPLIANCE-TO-OBJECT/INTELLIGENT APPLIANCEINTERACTION, U.S. Pat. No. 8,548,334, Issued on Oct. 1, 2013 and theentire contents of this US Non-Provisional Patent Application areincorporated herein.

Ultrathin Battery Of Portable Internet Appliance

An ultrathin organic battery utilizes push-pull organic molecules,wherein after an electron transfer process, two positively chargedmolecules are formed which are repelled by each other like magnets. Byinstalling a molecular switch an electron transfer process can proceedin an opposite direction. Thus, forward and backward switching of anelectron flow can form a basis of an ultrathin, light weight and powerefficient organic battery.

Wireless Charging of Portable Internet Appliance

The portable internet appliance 1600 can be electrically charged via aresonant electromagnetic inductive coupling energy transfer without anyphysical wire.

Authentication by Portable Internet Appliance

The portable internet appliance 1600 can be integrated into a miniatureRaman spectrophotometer. The miniature arrayed waveguide gratings Ramanspectrophotometer can be inserted into the USB port of the portableinternet appliance 1600. The Raman spectrophotometer can authenticate aproduct by scanning the product in Raman multispectral mode formolecular vibrational spectrum. For example, the Raman spectrophotometercan authenticate a check/banknote, wherein the check/banknote isintegrated with a nano-scaled barcode. The nano-scaled barcode can be anarray of a unique combination of fluorescent nanoparticles. Furthermore,each fluorescent nanoparticle/Raman tag (as described in previousparagraph) can be embedded with an optical nanoantenna to increase theRaman signal, if needed. The fluorescent nanoparticles/Raman tags withembedded nanoantenna can be caged within a bit larger nanocontainer(e.g., a boron nitride nanotube/carbon nanotube). Thus, the miniatureRaman spectrophotometer can enable product authentication.

Biological Lab-On-A Chip of Portable Internet Appliance

A biological lab-on-a-chip is a module that integrates a fewbio-analytical functions on a single chip to perform point-of-caredisease diagnostics. For example, a miniature biological lab-on-a-chipmodule manufactured by Ostendum can be integrated (by inserting into anelectro-mechanical cavity of the portable internet appliance 1600) intothe portable internet appliance 1600 to perform point-of-care diseasediagnostics reliably, quickly and economically. Such a lab-on-a-chipanalysis can be transmitted from the portable internet appliance 1600 toa physician and/or a hospital for an interpretation without human input.

In addition, holographic images of the complete gene sequence of theuser can be stored in the portable internet appliance 1600 to enable aphysician/surgeon to design a personalized medical treatment.

Ionized Gas Cloud Based Cooling Component of Portable Internet Appliance

Many algorithms, as discussed above can consume significant electricalpower due to computational complexities. Alternatively, many algorithmscan be processed at a secure remote/cloud based data storageunit/server. Details of an ionized gas cooling component for themicroprocessor or system-on-chip have been described/disclosed in U.S.Non-Provisional patent application Ser. No. 13/448,378 entitled “SYSTEM& METHOD FOR MACHINE LEARNING BASED USER APPLICATION”, filed on Apr. 16,2012 and the entire contents of this US Non-Provisional PatentApplication are incorporated herein.

An ionized gas cloud based cooling component has an array of negativevoltage biased nano-scaled tips (e.g., nano-scaled tips can befabricated/constructed, utilizing boron nanotube/carbonnanotube/amorphous diamond/tungsten), wherein each nano-scaled tip isplaced just below a micro-scaled hole (e.g., about 50-100 microns indiameter) of positive voltage biased surface (e.g.,tungsten/two-dimensional crystal material (e.g., graphene)). Electronsemitted from the negative voltage biased array of nano-scaled tips canescape through the array of micro-scaled holes and ionize the gasmolecules within the boundaries of a heat sink (e.g.,aluminum/silicon/copper/carbon nanotube/carbon nanotube-coppercomposite/diamond). By switching the voltage polarity of the heat sink,a moving ionized gas cloud can disperse/dispose the heat from thesystem-on-chip.

However, it is desirable that an array of nano-scaled tips emitelectrons at a much lower voltage (e.g., at 5 volts). An array ofnano-scaled tungsten tips can be fabricated/constructed, utilizing atungsten substrate. The array of nano-scaled tungsten tips can besurrounded by an insulator. The array of nano-scaled tungsten tips canbe decorated with a monolayer(s) of material(s)—in particular amonolayer of diamond, deposited by low temperature electron cyclotronresonance chemical vapor deposition or a monolayer of gold deposited byradio frequency magnetron sputtering to enable electron emission at muchlower voltage (e.g., at 5 volts) through the micro-scaled hole, which isfabricated/constructed, utilizing tungsten material.

Fixed or Reconfigurable Outer Case/Package of Portable InternetAppliance

The outer case/package of the portable internet appliance 1600 can befabricated/constructed, utilizing a biodegradable material as describedin the Table-15.

TABLE 15 Compositions Of A Biodegradable Plastic Material For PortableInternet Appliance Com- Wt % Wt % Wt % Wt % positions Material AMaterial B Material C Material D 1 80% Lignin 20% Chitin 2 80% Lignin20% Chitosan 3 80% Lignin 10% Chitin 10% Chitosan 4 80% Lignin 20%Fibroin 5 80% Lignin 10% Chitin 10% Fibroin 6 80% Lignin 10% Chitosan10% Fibroin 7 80% Lignin 10% Chitosan 10% Fibroin 8 80% Lignin 5%Chitosan 5% Chitosan 10% Fibroin

The aluminum/magnesium alloys have small building blocks-callednanocrystal grains and crystal defects. Nanocrystal grains with crystaldefects are mechanically stronger than perfect aluminum/magnesiumcrystals.

The outer case/package of the portable internet appliance 1600 can beconstructed from a nano-engineered aluminum/magnesium alloy or a liquidmetal alloy or a carbon fiber/carbon nanotube-polymer composite material(carbon fiber/carbon nanotubes embedded within injection mold of amolten polymer) or a carbon fiber/carbon nanotube-polymer compositematerial with magnesium metal.

Furthermore, an antenna can be constructed from a carbon fiber embeddedwith a conducting polymer or metal.

The outer case/package of the portable internet appliance 1600 can befabricated/constructed, utilizing a suitable material matrix with anarray of shape memory changing material wires (e.g., shape memorychanging polymer wires).

Furthermore, the shape memory changing material matrix can be added with1 wt % to 10 wt % graphene (or 1 wt % to 10 wt % graphene likenanostructural material) and/or 1 wt % to 10 wt % nanotubes (e.g., boronnitride/carbon) to form a nanocomposite.

Additionally, carbon nanotubes (by stamping onto the shape memorychanging material matrix/nanocomposite) can serve as a scaffold forgrowing zinc oxide nanostructure. Zinc oxide is a piezoelectricsemiconductor material (it generates an electric potential after amechanical motion). Zinc oxide nanostructures are nearly transparent andthey can be used for touch-sensitive active matrix arrays on top adisplay matrix.

Furthermore, the above nanocomposite can be integrated (e.g.,multi-layered/mixed) with (a) lignin (or lignen) and/or (b) chitin (abiopolymer based on the N-acetyl-glucosamine monomer) and/or (c)chitin's variant deacetylated counterpart chitosan and/or (d) fibroin (aprotein derived from silk).

For flexibility/stretchability, a nanotube (e.g., carbon nanotube) basedmicroprocessor can be embedded in a flexible/stretchable substrate,which has both conductive and non-conductive regions.

By way of an example and not by way of any limitation, a flexiblesubstrate can be hydrogel/chitosan/fibroin/poly(lactic-co-glycolic acidembedded with regions of nanotubes or a suitable combination ofchitosan, fibroin and poly(lactic-co-glycolic acid) embedded withregions of nanotubes or a suitable combination of hydrogel, chitosan,fibroin and poly(lactic-co-glycolic acid) embedded with regions ofnanotubes.

By way of an example and not by way of any limitation, a flexiblesubstrate of hydrogel/chitosan/fibroin/poly(lactic-co-glycolic acidembedded with regions of nanotubes) or a suitable combination ofchitosan, fibroin and poly(lactic-co-glycolic acid embedded with regionsof nanotubes) or a suitable combination of hydrogel, chitosan, fibroinand poly(lactic-co-glycolic acid embedded with regions of nanotubes) canact as a flexible/stretchable sensor.

The portable internet appliance 1600 can be flexible and stretchable,when it is integrated with a flexible electrophoretic plastic display,flexible transparent electronics chipset, printed battery (e.g., Zn—MnO₂printed battery) and zinc oxide nanowire based solar cell component(photosensitive dye molecules can be anchored to an array of zinc oxidenanowires to fabricate/construct a solar cell component).

Other Algorithms of Portable Internet Appliance in Healthcare

The portable internet appliance 1600 can include an algorithm forinterpreting a user's communication in a natural language, wherein thealgorithm for interpreting communication in a natural language is storedin a local data storage unit of the portable internet appliance 1600 ora cloud based data storage unit. The portable internet appliance 1600can include an algorithm for generating social graph/personal analytics,wherein the algorithm for social graph/personal analytics generation isstored in a local data storage unit of the portable internet appliance1600 or a cloud based data storage unit.

Example Applications of Portable Internet Appliance in Healthcare

A biosensor (integrated with a low-power wireless transceiver such asBroadcom's BCM20732) can measure a user's heart rhythm. The lab-on-chip(integrated with a low-power wireless transceiver such as Broadcom'sBCM20732) can measure the user's cardiovascular rhythm pattern(s). Boththe biosensor and lab-on-chip can transmit data to the portable internetappliance 1600.

The portable internet appliance 1600 can compare the newly measured datawith previously stored data of the user and if the newly measured datais significantly abnormal, the portable internet appliance 1600 canimmediately communicate (indicating the location and condition of theuser) with the user's personal physician and/or directly communicatewith 911 emergency without the user input.

FIG. 18B illustrates how the portable internet appliance 1600 can bemorphed into a small form factor (multi-purpose) programmable smartcard. Additionally, a smart card can contain a nanotube (e.g., boronnitride/carbon) based microprocessor.

Furthermore, a stand-alone wristwatch-style device as illustrated inFIG. 18C can be wirelessly tethered to the portable internet appliance1600. The standalone wristwatch-style device can befabricated/constructed, utilizing a wraparound display on a flexiblesubstrate (e.g., DuPont Kapton or Corning Willow glass).

Organic light emitting diodes that do not need backlighting, arebrighter with a wider viewing angle and better color contrast andorganic light emitting diodes can be printed on the flexible substrate.

Furthermore, the above flexible substrate can be integrated with amicroprocessor, memory/data storage, a sensor/an array of sensors (e.g.,bio/health sensors), a low-power radio and a thin-film battery.

The stand-alone wristwatch-style device can be integrated with an imagesensor based on graphene. Additionally, the stand-alone wristwatch-styledevice can be integrated with a microphone for voice activation toenable the user's voice instructions and/or authentication.

Furthermore, the standalone wristwatch-style device can pull relevantinformation (e.g., an appointment calendar, e-mail, twitter notificationand short picture chat) from the portable internet appliance 1600, sothe user can absorb information with a mere glance and caninteract/communicate with the portable internet appliance 1600.

As illustrated in FIG. 18C, the stand-alone wristwatch-style device canbe connected (by wire or wirelessly) with a Lifepatch of an array ofbio/health sensors (e.g., a sensor for blood pressure/blood sugar/heartrate/oxygen level).

FIG. 18D illustrates a block diagram of a LifeSoC for the Lifepatch.LifeSoC has digital signal processing, memory management and powermanagement capabilities; wherein LifeSoC is interfacing with variousbio/health sensors (e.g., blood pressure, ECG, EEG, skin hydration,stress and oximetry) and low power wireless devices (e.g.,Wibree/Bluetooth) and near-field communication. Furthermore, LifeSoC canbe fabricated/constructed on a flexible/stretchable substrate.

FIG. 18E illustrates how a nanoI/O connects/communicates with othernanoI/Os via nanolinks. An array of nanoI/Os connects/communicates witha nanorouter via nanolinks. The nanorouter or the array of nanoroutersconnects/communicates with an object. The object or the array of objectsconnects/communicates with a router via objectlinks. The router or thearray of routers connects/communicates with portable internet appliances1600 via the internet. Such interactions as described in FIG. 18E canenable real-time tracking of consumer behavior, real-time awareness (ofhealth/environment), real-time sensor-driven decision analytics andcomplex autonomous systems.

FIG. 18F illustrates a block diagram of a nanoI/O and a block diagram ofa nanorouter. The nanoI/O integrates a nano-scaled processor(nanoprocessor), a nano-scaled memory (nanomemory), a nano-scaled sensor(nanosensor), a nano-scaled actuator enabled molecular transmitters anda single molecule organic (e.g., polythiophene) light emitting diode. Itshould be noted that the single molecule organic light emitting diodeand/or an array of nano-scaled actuator enabled molecular (e.g.,pheromone) transmitters, can be activated upon the nanosensor's signal.

The nanoprocessor, nanomemory and nanosensor can befabricated/constructed on silicon with nanopillars of non-siliconsemiconductor materials (e.g., gallium arsenide, gallium nitride andindium phosphide on silicon) and nanowires connecting betweennanopillars of non-silicon semiconductor materials.

Furthermore, the nanoprocessor can be fabricated/constructed as an arrayof nanowire transistors/switches. The array of nanowiretransistors/switches can be nonvolatile. Nonvolatile nanowiretransistors/switches can remember when no electrical power is applied tononvolatile nanowire transistors/switches—thus enabling extremely lowelectrical power consumption.

Furthermore, nonvolatile nanowire transistors/switches can integratememristors enabling neuron-like analog or learning nanoprocessor.

Nanomemory cells can be fabricated/constructed of molybdenum disulphidewith graphene in a two-dimensional hetrostructure, where molybdenumdisulphide acts as a channel in intimate contact with grapheneelectrodes in field-effect transistor configurations.

Alternatively, bistable rotaxane molecule based crossbar nanomemorycells can be fabricated/constructed, wherein a nanomemory cell consistsof two perpendicular layers of nanowires, providing voltage, reading andwriting information in bistable rotaxane molecule. A bistable rotaxaneis a dumbbell-shaped molecule of a rod section and terminated by twostoppers, further encircled by a ring. The bistable rotaxane moleculecan act as an electrical switch by incorporating two differentrecognition sites for the ring and the ring sits preferentially at oneof the two recognition sites. The bistable rotaxane molecule can act asan electrical switch, provided the ring can be induced to move from onerecognition site to the other recognition site and then reside there forminutes. The bistable rotaxane molecules can be electrically switched ata very modest voltage from an off (low conductivity) state to an on(high conductivity) state.

The nanorouter integrates a nanoprocessor+ (a bit more powerful thannanoprocessor), nanomemory+ (a bit more powerful than nanomemory),molecular receivers with synthetic receptors and a quantum dot detector(e.g., a nanogap quantum dot detector). Light and/or molecules (e.g.,pheromone) transmitted by a nanoI/O can be detected by a quantum dotdetector and an array of synthetic molecular receptors respectively.

The signals received by the nanorouter from nanoI/Os are similar toquorum sensing.

It should be noted that a nanoprocessor++ is a bit more powerful than ananoprocessor+ and a nanomemory++ is a bit more powerful than ananomemory+.

FIG. 18G illustrates a configuration of an object, which is anano-scaled system-on-package (SoP) of a nanoprocessor++, ananomemory++, a nanostorage for tiny instructions (which can be eitherembedded in the nanostorage at the very onset or wirelesslytransmitted/reconfigured to be stored in the nanostorage at a latertime), a wireless nanotransceiver (e.g., a terahertz bandnanotransceiver based on silicon-germanium heterojunction bipolartransistors or a hybrid silicon-germanium and gallium nitride baseddevice enhanced with graphene), a nanoantenna (e.g., graphene basednanoantenna), an array of quantum dot nanodetectors, an array ofnano-scaled solar cells (e.g., a nanoassembly of gold nanoparticles withorganic porphyin molecules) as nanosolar cells integrated with anano-scaled lens to capture sunlight, a nano-scaled sensor, an array ofself-assembled superlattices of silver clusters on a two-dimensionalmaterial (e.g., graphene) as an array of molecular sensors and ananowire battery (e.g., piezoelectric zinc oxide nanowires basednanogenerator).

Furthermore, the nanosolar cells can be three-dimensional nanosolarcells. An array of three-dimensional nanosolar cells (each nanosolarcell is about 5 microns by 5 microns in area, 100 microns tall andseparated from each other at about 10 microns) can utilize a siliconsubstrate, as the nanosolar cells' bottom electrode. A thin-film of ironis deposited and patterned on the silicon wafer by photolithography.Vertically aligned multi-walled carbon nanotubes can be seeded and grownon the patterns of thin-film of iron, utilizing 700 degrees' centigradechemical vapor deposition with hydrocarbon gases, wherein the carbon andhydrogen are separated. Upon formation of arrays of vertical carbonnanotubes, a p-type photovoltaic layer (e.g., cadmium telluride (CdTe))and an n-type photovoltaic layer (e.g., cadmium sulfide) can beconformally grown by molecular beam epitaxy (MBE).

In singlet-exciton fission, an arriving photon from the sunlight cangenerate two (2) excitons (excited states) yielding two (2) electrons.Pentacene generates two (2) excitons (excited states) yielding two (2)electrons in a narrow visible spectrum of the sunlight. Pentacene and/orother suitable materials for singlet-exciton fission in another spectrumof the sunlight can be integrated via coating or wafer stacking/bonding(wafer stacking/bonding is useful, when the material is not suitable forcoating) for enhanced electron generation.

A thin-film of conducting transparent indium tin oxide/graphene layercan act as the top electrode.

Furthermore, a photovoltaic material can be integrated (e.g., doped)with a light sensitive compound/protein.

Furthermore, a photovoltaic material can be integrated with a lighttrapping structure or an optical metamaterial based light trappingstructure for light collection from many incident angles. The lighttrapping structure or an optical metamaterial based light trappingstructure can be deposited directly onto the photovoltaic material.Alternatively, the light trapping structure or an optical metamaterialbased light trapping structure can be deposited on a suitable substrateand stacked/bonded (e.g., Soitec company's smart stacking layer transfertechnology for processed wafers).

A nanostorage device for instructions in the form ofwrite-once-read-many times can be fabricated/constructed of a DNA basedmemory cell, which is DNA embedded with silver nanoparticles sandwichedbetween two transparent electrodes. An incident ultraviolet light(through one of the transparent electrodes) can cause the silver atomsto nanocluster for data encoding. When a low voltage is applied throughthe electrodes to ultraviolet-irradiated DNA, only a low current is ableto pass through the memory cell. This corresponds to the off state. But,when the applied voltage exceeds a certain threshold, an increasedcurrent is able to pass through the memory cell—this corresponding tothe on state. It is reversible from the off state to the on state. Oncethe memory cell is turned on, it stays on, no matter what voltage isapplied to the memory cell.

A self-assembled superlattice consists of silver clusters, wherein eachsilver cluster has a core of 44 silver atoms. Thirty-three molecules ofmercaptobenzoic acid (p-MBA) can be utilized to protect the silverclusters. Mercaptobenzoic acid molecules are attached to the silveratoms by sulfur atoms. By compressing the self-assembled superlattice,the hydrogen bonds attached to the p-MBA molecules, rotate about25-degrees angle and return to their original position—creating amolecular gear machine.

By integrating conductive polymers with the self-assembled superlatticeof silver clusters on a substrate of a two-dimensional material, theself-assembled superlattice of silver clusters can be utilized asmolecular sensors.

DNA nanostructures preferentially attached to lithographically patternedbinding/assembly sites can be utilized as a nanoprinted circuit board(nanoPCB) to fabricate/construct a nanoI/O, a nanorouter and an objectby sticking nano-scaled components of the nanoI/O or the nanorouter orthe object.

FIG. 18H illustrates another configuration of the object, wherein thestacked package is realized by a standard microelectronics packagingmethod.

The object can be encapsulated for protection from the environment.Furthermore, ambient backscattering of existing wireless signal(s) canenable an object as a sensor to communicate with another object as asensor without an electrical powering device.

The object can sense/measure/coordinate its actions via a sharedlanguage (e.g., AllJoyn or Message Queue Telemetry Transport (MQTT)).AllJoyn provides a universal software framework. Message Queue TelemetryTransport is an open message protocol. Collective intelligence (e.g.,swarm intelligence) can be derived from inputs of networks ofobjects/biological objects.

Example Applications of Portable Internet Appliance for Point-of-CareDetection of a Disease/an Array of Diseases

The portable internet appliance 1600 can be suitably integrated with aphotonics-lab-on chip for point-of-care detection of a disease/an arrayof diseases.

Various embodiments of a photonics-lab-on-chip are illustrated in FIGS.19A, 19B, 19C, 19D, 19E, 19F, 19G, 19H, 19I and 19J.

In FIG. 19A an array of light sources (e.g., an edge emittingdistributed feedback (DFB) wavelength tunable laser or amicroelectro-mechanical-system enabled wavelength tunable surfaceemitting vertical cavity laser-integrated with a 45-degrees anglemirror) is guided via an array of optical waveguides.

The array of optical waveguides is connected with a fluidic channel,which contains disease specific fluorescent biomarker binders tochemically bind with disease specific biomarkers in a human body'sblood/biological fluid. A fluorescent biomarker binder is a biomarker,which is chemically coupled with a fluorophore or a photoswitchablefluorophore.

Furthermore, each fluorescent biomarker binder can be integrated orcoupled with a three-dimensional protruded structure (e.g., an opticalantenna) to enhance fluorescence significantly.

The fluidic channel is optically connected with a cylindrical lens tocollimate the output fluorescent beam to an array of charged-coupleddetectors based cameras for spectrum analysis.

Alternatively, in FIG. 19B, the cylindrical lens can be replaced by anarray of high Q ring resonator based add filters. The outputs of thehigh Q ring resonators based add filters can be combined at one port.This combined port can be the input of a high-resolutionspectrophotometer for spectrum analysis.

In FIG. 19C, a light source is guided via an array of optical waveguides(e.g., MMI/Y-branched waveguides). The array of optical waveguides isconnected with a fluidic channel, which contains disease specificfluorescent biomarker binders to chemically bind with disease specificbiomarkers in a human body's blood/biological fluid.

Furthermore, each fluorescent biomarker binder can be integrated with anoptical antenna to enhance fluorescence significantly.

The fluidic channel is optically connected with a cylindrical lens tocollimate the output fluorescent beam to an array of charged-coupleddetectors based cameras for spectrum analysis.

Alternatively, in FIG. 19D, the cylindrical lens can be replaced by anarray of high Q ring resonator based add filters. The outputs of thering resonators based add filters can be combined at one port. Thiscombined port can be the input of a high-resolution spectrophotometerfor spectrum analysis.

By way of an example and not by way of any limitation, a high-resolutionspectrophotometer can be echelle gratings baseddemultiplexer/microspectrophotometer-on-a-chip/photonic crystal/planarlightwave circuit based demultiplexer/microring resonator based/siliconnanowire waveguide based demultiplexer spectrophotometer.

Alternatively, a high-resolution spectrophotometer can be aFourier-transform (FT) Michelson-type arrayed waveguide gratingsspectrophotometer. The spectral resolution of the Fourier-transformMichelson-type arrayed waveguide gratings spectrophotometer can beincreased by inserting a triangular photonic bandgap waveguide sectioninto the waveguide array. Furthermore, the Fourier-transformMichelson-type arrayed waveguide gratings spectrophotometer can befabricated/constructed by two interleaved arrayed waveguide gratingsthat produce interference fringes with different spacing for differentwavelengths.

FIG. 19E illustrates a specific embodiment of 19D. Y-branched opticalwaveguides are connected to an array of fluidic channels, wherein eachfluidic channel contains disease specific fluorescent biomarker bindersto chemically bind with disease specific biomarkers in a human body'sblood/biological fluid. Furthermore, any branched optical waveguides(e.g., MMI waveguide) can function instead of Y-branched opticalwaveguides.

Furthermore, each fluorescent biomarker binder can be integrated with anoptical antenna to enhance fluorescence significantly.

Laser light propagating through Y-branched optical waveguides can inducefluorescence signals in the array of fluidic channels. The fluidicchannels are separated spatially enough to reduce fluorescence relatedcross-talk from one fluidic channel with another fluidic channel.Fluorescence from each fluidic channel is picked up by a suitable high Qring-resonator filter and multiplexed/combined at the exit port of thering-resonator filter device, which is coupled with theFourier-transform Michelson-type arrayed waveguide gratingsspectrophotometer/an array of photodiodes for spectrum analysis.

However, it should be noted that a ring resonator basedspectrophotometer/an array of photodiodes can be utilized for spectrumanalysis.

FIG. 19F illustrates a planar design of a photonics-lab-on chip. Theplanar design has a fluid cavity which contains a human body'sblood/biological fluid and disease specific fluorescent biomarkerbinders to chemically bind with disease specific biomarkers in a humanbody's blood/biological fluid.

The fluid cavity is optically connected by an input optical waveguideand an output optical waveguide. The input optical waveguide isconnected with an optical excitation source (e.g., a laser). The outputoptical waveguide is connected to an arrayed waveguide gratingsspectrophotometer and an array of photodiodes for spectrum analysis.

The planar design in FIG. 19F can be scaled to an array of fluidcavities, an array of input optical waveguides, an array of outputoptical waveguides, an array of arrayed waveguide gratingsspectrophotometers and multiple arrays of photodiodes. The scaledversion of the planar design is illustrated in FIG. 19G.

Alternatively, as illustrated in FIG. 19H just one arrayed waveguidegratings spectrophotometer/an array of photodiodes can be utilized inconjunction with an array of lasers, an array of micromirrors, an arrayof absorbers, an array of optical waveguides, an array of fluidcavities-containing a human body's blood/biological fluid and diseasespecific fluorescent biomarker binders to chemically bind with diseasespecific biomarkers in a human body's blood/biological fluid.

FIG. 19I illustrates another embodiment of 19D, wherein an array ofbranched optical waveguides is replaced by an array of opticalwaveguides, integrated with an optical switch and a power/wavelengthsplitter.

FIG. 19J illustrates another embodiment of 19I, wherein an array of highQ ring resonator based add filters is also replaced by an array ofoptical waveguides, integrated with an optical switch and apower/wavelength splitter.

Additionally, a metamaterial waveguide (e.g., a hyperbolic waveguide) ofalternating ultra thin-films of semiconductors and/or insulators andmetals can be fabricated/constructed to absorb each wavelength of light,at slightly different places in a vertical direction.

Additionally, various devices can be connected by a multi-optical fiberconnector, making the fluid/cavity section(s) containing a human body'sblood/biological fluid disposable.

Alternatively, optical fibers can be aligned passively with precisemetal alignment pins seated into v-grooves on a precise silicon opticalbench substrate. The precise metal alignment pins can be utilized topmate with a pluggable optical fiber connector integrated with a moldedplastic lens.

FIG. 19K illustrates an embodiment of an ultra-fast Bose-Einsteincondensate based ultra-fast optical switch for applications in biology.An ultra-fast N×N Bose-Einstein condensate based optical switch can berealized, utilizing an array of single-mode/multi-mode waveguides on theleft-hand side and an array of single-mode/multi-mode waveguides on theright-hand side, wherein the array of single-mode/multi-mode waveguideson the left-hand side and the array of single-mode/multi-mode waveguideson the right-hand side are optically coupled with polaritonBose-Einstein condensate. Short-lived room temperature polaritonBose-Einstein condensate can be created through the interaction of alaser light (bouncing back and forth within multiple dielectricthin-films) and a luminescent polymeric thin-film of about 30 nanometersin thickness. The luminescent polymeric thin-film is embedded withinmultiple dielectric thin-films, wherein the multiple dielectricthin-films is then illuminated from the bottom (of the multipledielectric thin-films, each dielectric thin-film is about 40 nanometersin thickness) by a vertical surface emitting laser or an in-plane laserintegrated with a mirror and a lens.

FIGS. 19L, 19M and 19N illustrate an integrated device to obtain nativemolecular components (e.g., DNA/mRNA/miRNA/piRNA/rRNA/tRNA) andproteins—as biomarkers, which were once caged within exosomes from ahuman body's blood/biological fluid. These native molecular componentscan be representative of the cell of origin.

FIG. 19L illustrates a biochemical chamber to obtain native biologicalmolecular components and/or proteins—as the biomarkers, which were oncecaged within exosomes.

The biochemical chamber can be molded in poly(dimethylsiloxane). Thebiochemical chamber is degassed via vacuum prior to its use and theabsorption of gas by poly(dimethylsiloxane) provides the mechanism foractuating and metering the flow of fluid in the microfluidic channelsand between various parts of the biochemical chamber. The biochemicalchamber can take in a human body's blood at inlets. The biochemicalchamber can use tiny microfluidic channels of 30 microns in diameterunderneath the inlets to separate the serum from a human body's blood,by utilizing laws of microscale physics. The serum moves through thebiochemical chamber via a process called degas-driven flow.

Superparamagnetic nanoparticles iron oxide can be synthesized with apositive electrical charge to bond onto the membrane surface of exosomes(within a human body's blood/biological fluid) of negative electricalcharge due to electrostatic interactions. Capture of exosomes bysuperparamagnetic nanoparticles iron oxide can be realized inCapture+Wash Microchamber. The biochemical chamber can be integratedwith a magnet. Exposure to a magnetic field can separatesuperparamagnetic nanoparticles iron oxide bonded with exosomes.

Alternatively, the biochemical chamber can be integrated with ananosieve/nanomembrane (e.g., a carbon nanomembrane) of about 100nanometers pore diameter to filter exosomes—this is not illustrated inthe Lysis+Probe Microchamber of the FIG. 19L.

Alternatively, the biochemical chamber can be integrated with ananofilter (e.g., a carbon nanomembrane) of about 100 nanometers porediameter to filter exosomes. For example, a nanofilter can be graphenebased nanofilter. Nanoholes in graphene-a hexagonal array of carbonatoms can be fabricated/constructed in a two-stage process. First, agraphene sheet is bombarded with gallium ions or helium ions, whichdisrupt the carbon bonds. Second, the graphene sheet is etched in anoxidizing solution that reacts strongly with the disrupted carbonbonds-producing a nanohole at each spot where the gallium ions or heliumions struck. By controlling how long the graphene sheet is left in theoxidizing solution, one can control the average size of the nanoholes.

Alternatively, the biochemical chamber can be integrated with abiological probe, wherein a modified first end (e.g., the first end ismodified with one/two lipid tail(s)) of the biological probe canchemically bind/couple/attach with an exosome, wherein a second end ofthe biological probe containing a biotin molecule, wherein the biotinmolecule can chemically bind/couple/attach with an avidin molecule,attached on a surface modified magnetic bead (e.g., a magnetic bead of300-500 nanometers in diameter). Capture of exosomes by the biologicalprobe is realized in Capture+Wash Microchamber.

The Lysis+Probe Microchamber is removable. Furthermore, a suitablechemical (e.g., System Bio company's Micro SeraMir) can be added in theremovable Lysis+Probe Microchamber to break the membrane of exosomes toobtain embedded a disease specific molecular components and/orproteins—as the biomarkers, which were once caged within the exosomes.

The removable Lysis+Probe Microchamber has a disease specific aptamer(integrated with a fluorescent protein/fluorophore/photoswitchablefluorophore) to bind with a-disease specific molecular components and/orproteins, which were once caged within the exosomes.

The removable Lysis+Probe Microchamber has a disease specific designerprotein (integrated with a fluorescentprotein/fluorophore/photoswitchable fluorophore) with a leave-one-outconfiguration, wherein each protein has an omitted segment to create abinding site to fit a disease specific protein, which was once cagedwithin the exosomes.

The removable Lysis+Probe Microchamber has a disease specificsynthetically designed biomarker binder (e.g., an aptamer or asynthetically designed biological sensor for nucleic acid/syntheticallydesigned gene circuit) integrated with a fluorescentprotein/fluorophore/photoswitchable fluorophore to fit with a diseasespecific native molecular component—as the biomarkers, which were oncecaged within the exosomes.

FIG. 19M illustrates an embodiment of the removable Lysis+ProbeMicrochamber with a biomarker binder (integrated with a fluorescentprotein/fluorophore/photoswitchable fluorophore).

FIG. 19N illustrates an embodiment of the removable Lysis+ProbeMicrochamber with a biomarker binder such as a designer protein(integrated with a fluorescent protein/fluorophore/photoswitchablefluorophore). The designer protein is a leave-one-out configuration,wherein each protein has an omitted segment to create a binding site tofit a disease specific protein, which was once caged within theexosomes.

One or more three-dimensional protruded structures can be integratedwith the fluorescent protein/fluorophore/photoswitchable fluorophore toenhance fluorescence.

Alternatively, the removable Lysis+Probe Microchamber has an array ofthree-dimensional protruded structures at or near the bottom of theRemovable Lysis+Probe Microchamber to enhance fluorescence.

The one three-dimensional protruded structure can include generally athin-film, wherein the thin-film can include a single crystallinestructure metal or a polycrystalline structure metal or a metal nitride,wherein a dimension or shape of the one three-dimensional protrudedstructure is varied for maximum enhancement of the fluorescenceemission, wherein more than the one three-dimensional protrudedstructure is spaced or arranged in a one-dimensional array or in atwo-dimensional array, wherein the one-dimensional array ortwo-dimensional array is a systematic arrangement of similarthree-dimensional protruded structures, wherein a pitch or a gap or aduty cycle of the one-dimensional array of the three-dimensionalprotruded structures is varied for maximum enhancement of thefluorescence emission, wherein a pitch or a gap or a duty cycle of thetwo-dimensional array of the three-dimensional protruded structures isvaried for maximum enhancement of the fluorescence emission, wherein thefluorescent protein/fluorophore/photoswitchable fluorophore ispositioned at a specified location with respect to the onethree-dimensional protruded structure, as described in previousparagraphs.

The fluidic channel as described in FIGS. 19A, 19B, 19C, 19D, 19E, 19Iand 19J can be replaced with the removable Lysis+Probe Microchamber, asdescribed in either FIG. 19M or FIG. 19N.

The cavity, as described in FIGS. 19F, 19G and 19H, can be replaced withthe removable Lysis+Probe Microchamber, as described in either FIG. 19Mor FIG. 19N.

The optical diagnostic biomodule described in FIGS. 12V, 12X1 and 12Ycan be utilized to detect the fluorescence emission, identifyingspecific native molecular components and/or proteins—as the biomarkers.The optical diagnostic biomodule described in FIGS. 14C and 14J can bealso utilized to detect DNA sequencing (which can be also utilized forexome sequencing and RNA sequencing), identifying specific nativemolecular components, as the biomarkers.

The electrical diagnostic biomodule described in FIG. 14A can beutilized to detect DNA sequencing (which can be also utilized for exomesequencing and RNA sequencing), identifying specific native molecularcomponents, as the biomarkers.

Alternatively, a femtosecond laser (as a single machining tool) can beutilized to fabricate/construct three-dimensional optical waveguides andfluidic channels of the photonics-lab-on chip. Thus, thephotonics-lab-on chip can be utilized for point-of-care detection of adisease/an array of diseases.

FIG. 19O illustrates (both in top view and cross-sectional view) ananoscope for detecting various RNAs and proteins within exosomes from ahuman body's blood/biological fluid. A specific RNA and/or protein canbind with a specific aptamer, wherein the aptamer is chemically coupledwith a quantum dot fluorophore. An incident light from a laser,collimated by a lens and transmitted through an optical filter, thenfocused onto a nanotray containing exosomes, by surface plasmonpolaritons based a nanofocusing waveguide lens.

Alternatively, an atomic force microscopy tip with high resolutionoptics (100×, resolving power ≤400 nanometers) can be utilized as ananofocusing waveguide lens.

The bottom of the nanotray can be integrated with an array of goldnanoantennas for light amplification. The nanotray can be mounted on amovable stage.

The nanofocusing waveguide lens is fabricated/constructed, utilizingamorphous silicon dioxide. The waveguide is coated with an ultrathin-film of gold. The nanofocusing waveguide lens is about 5 micronslong and rectangular in shape tapering to a point at one end. Becausethe nanofocusing waveguide lens concentrates light into a nanosizedpoint, it can create a high-resolution map of RNAs and proteins withinexosomes. The nanofocusing waveguide lens is mounted and enclosed withina rotating enclosure.

Fluorescence light can also travel in the reverse/opposite directionthrough the nanofocusing waveguide lens, then through the opticalfilter, the lens and the photodiode. Thus, collecting light through thenarrow point can turn the nanofocusing waveguide lens into a highresolution nanoscope.

However, it should be noted that FIG. 19O illustrates the nanoscope in avertical configuration. Other configurations (e.g., an upright or aninverted or a planar configuration) of the nanoscope are possible,without departing from the scope and spirit of this nanoscope.

FIG. 19P illustrates an array of nanoscopes enabled bymicroelectro-mechanical-system mirror array (e.g., Texas Instrument'sDigital Light Processor projector chip) and rotating array of enclosuresfor nanofocusing waveguide lens.

FIG. 19Q illustrates a plasmonic interferometer for detecting variousRNAs and proteins within exosomes from a human body's blood/biologicalfluid. A quartz substrate coated with a thin-film of silver (about 300nanometers in thickness). Fabricated/constructed in silver thin-film isa nano-scaled plasmonic interferometer, wherein the nano-scaledplasmonic interferometer has a center slit (about 100 nanometers indepth and 30 microns in length) with a groove (about 70 nanometers indepth, 130 nanometers in width and 30 microns in length) on each side ofthe groove. When light (e.g., light from a narrow-band light source) isshone through the quartz substrate, the groove causes a wave of freeelectrons in the silver thin-film, a surface plasmon polariton topropagate toward the center slit. Those waves interfere with light thatpasses through the center slit. A sensitive spectrophotometer/opticalfiber assembly (as described in the FIG. 19R) can be utilized to measurethe patterns of interference generated by the grooves and slit. When ahuman body's blood/biological fluid is deposited on the abovenano-scaled plasmonic interferometer; the light and the surface plasmonwaves propagate through a human body's blood/biological fluid beforethey interfere with each other—thus altering the interference patterndetected by a sensitive spectrophotometer.

Furthermore, by adjusting the distance between the grooves and centerslit, the above nano-scaled plasmonic interferometer can be calibratedto detect the signature of a disease specific biomarker and/or bioactivecompound and/or bioactive biomolecule with high sensitivity in anextremely small volume of a human body's blood/biological fluid.

For example, a first enzyme-glucose oxidase can chemically react withglucose (from a human blood/biological fluid) to generate hydrogenperoxide. A second enzyme-horseradish peroxidase can chemically reactwith hydrogen peroxide to generate resorufin. Both reactions can befacilitated by microfluidic channels. Resorufin is a colored liquid,which can absorb/emit red light. Thus, the above nano-scaled plasmonicinterferometer can be calibrated to detect the signature of resorufin,as a measure of glucose concentration in a human body's blood/biologicalfluid.

Furthermore, thousands of nano-scaled plasmonic interferometers can befabricated in the thin-film of silver, wherein each nano-scaledplasmonic interferometer can be calibrated to detect only the signatureof a disease specific biomarker and/or bioactive compound and/orbioactive biomolecule with high sensitivity in an extremely small volumeof a human body's blood/biological fluid without any need of afluorophore.

FIG. 19R illustrates an optical assembly of plasmonicinterferometer-optical fiber-optical switch-spectrophotometer to measurethe interference patterns generated by an array of plasmonicinterferometers.

The interference patterns generated by the grooves and center slit ispropagated through an optical thin-film filter (to reduce cross-talkfrom other plasmonic interferometers) and focused by a focusing lensonto an optical fiber. The array of optical fibers is connected with aN×1 optical switch, which is optically connected with aspectrophotometer for spectrum analysis.

FIG. 20 illustrates the photonics-lab-on chip, which can be insertedinto the portable internet appliance 1600.

FIG. 20 also illustrates interactions of the portable internet appliance1600 with a hologram. A hologram is an optical illusion enabling atwo-dimensional image to appear in a three-dimensional form, out of theportable internet appliance 1600 and it can add a new dimension in videocalls and/or multimedia texts.

Furthermore, haptic feedback can be added to the hologram. A user cantouch and interact with the hologram and receive tactile responses, asif the hologram were real. Furthermore, various embodiments of hologramshave been described/disclosed described in U.S. Non-Provisional patentapplication Ser. No. 14/999,601 entitled “SYSTEM AND METHOD OFAMBIENT/PERVASIVE USER/HEALTHCARE EXPERIENCE”, filed on Jun. 1, 2016 andthe entire contents of this US Non-Provisional Patent Application areincorporated herein.

Example Applications of Portable Internet Appliance in Daily Life

The portable internet appliance 1600 can book the user on the nextflight, when the portable internet appliance 1600 finds out from theinternet and other resources that the previous flight is canceled. Theportable internet appliance 1600 can communicate with the user's familyabout the delay in arrival, newly booked flight and then notify/reorderthe airport shuttle/taxicab accordingly to pick up the user from theairport. Besides the internet, the other resources may include varioussearch engines (e.g., Bing, Google, Yahoo and Yelp), expert databases,data from existing Question & Answer forums (e.g., ChaCha) and answersdrawn from real-time applications that would ask relevant people if theyknow they answer. What makes the Question & Answer forums powerful isthat it keeps track of each and every question and answer pairing everasked and every answered ever given.

The portable internet appliance 1600 can order and pay (with near-fieldcommunication) for a coffee and downloadable movie (from a movie kiosk,utilizing Wi-Fi/millimeter wave (including 60 GHz)/terahertz bandtransceiver) of the user's preference at the airport terminal withoutthe user input, where the digital signature of the movie can expireafter a few days, making the movie unusable, after expiration of thedigital signature.

An indoor positioning system can track/map how and where the user spendstime both online and offline and if these times are happy or sad.

Example of Other Applications of Portable Internet Appliance in DailyLife

The portable internet appliance 1600 can be integrated with a suitablesoftware application program (“app”) to convert/merge both a cell phonenumber and an e-mail identification into one integrated useridentification.

FIG. 21 illustrates the merger of a cell phone number (213) 555-1212 andan e-mail identification mo@yahoo.com into one integrated useridentification: 213555.mo@lifepicasso.com. Thus, one integrated useridentification can be utilized as the focal point for (a) voice-over-IP,(b) texting with an attachment, (c) microtexting, (d) e-mail with anattachment and (e) convergence of various internet related services. Asan example, focal point of near real-time/real-time convergence ofvarious internet related services are: online files, VOIP phone calls,e-mails with attachments/text messages/voice messages/videomessages/social media messages, indoor positioning system/globalpositioning system locations, secure payments/purchases (offline/online)and digital banking data. The above convergence can be configured withencryption, time-shifted and follow-up capabilities.

Furthermore, the one integrated user identification can be utilized as aplatform for sending and receiving messages with another user.

FIG. 22A illustrates a hardware configuration of the one integrated useridentification with a processor, memory, a hard drive (storage device),a media server and an operating system, stored in a cloud baser server.The cloud based server also connects with a cloud based cognitivecomputer and the portable internet appliance 1600. The one integrateduser identification as a platform is shared between the sender'sportable internet appliance 1600 and the recipient's portable internetappliance 1600 over the internet.

Interactions of the users can be stored in a cloud based data storageunit and analyzed by a cloud based expert cognitive/learning computer innear real-time/real-time.

FIG. 22B illustrates a sender's portable internet cloud appliance (PICA)with a recipient's portable internet cloud appliance via a cloud basedserver, where the portable internet cloud appliance could be an internetconnected terminal device. The portable internet cloud appliance canreplace the portable internet appliance 1600.

FIG. 23 illustrates a near real-time/real-time focal point convergenceof various applications or functions with one integrated useridentification. APIs of many service links can be created by import.ioand converged into the one integrated user identification

For example, after properly authenticating the user's profile viasuitable biometric verification, the user can open a digital bankaccount entirely online. The digital bank account with a search box canenable the user to type in queries in a question-answer format (e.g.,“how much did I spend on travel last week?”).

Furthermore, the question-answer format can be enhanced by a fuzzy logicalgorithm/neuro-fuzzy logic algorithm. A fuzzy logic algorithm can beimplemented as follows: (a) define linguistic variables and terms, (b)construct membership functions, (c) construct rule base, (d) convertcrisp inputs into fuzzy values, utilizing membership functions(fuzzification), (e) evaluate rules in the rule base (inference), (f)combine the results of each rules (inference) and (g) convert outputsinto non-fuzzy values (de-fuzzification). The key idea of fuzzy logicalgorithm is that it uses a simple/easy way to secure the output(s) fromthe input(s), wherein the outputs can be related to the inputs by usingif-statements. Neural networks can approximate a function, but it isimpossible to interpret the result in terms of a natural language. Thefusion of neural networks and fuzzy logic in a neuro-fuzzy algorithm canprovide both learning as well as readability. A neuro-fuzzy algorithm isbased on combinations of artificial neural networks and fuzzy logic.

FIG. 24 illustrates patterns of various applications or functions of asingle user (as described in FIG. 23) with a user-centric personal web.A user-centric personal web can make life easier in automating routineactions/decisions for the user.

The personal web can relate to (a) social (the people, a user interactswith and the content the user exchanges in social networks), (b)location (the user checks into), (c) product (the things the user buyson Amazon or eBay, the movies the user watches on Snapchat/Netflix/YouTube or the hotels the user books online) and (d) interest (the sort ofthings the user searches for on Google/You Tube or the things the userlike on Facebook)—thus the personal web can reveal a lot about the user.

Building a statistical history, learning and relearning about the userdata of social, location, product and interest, the usefulness of apersonal web can be enhanced.

Thus, the portable internet appliance 1600 can be configured to knowwhat time the user wants to wake up at, even before the user set analarm. It knows the user's route to work and monitors traffic along theway, guiding the user through the most efficient route. Before theuser's lunch break, the user can get food recommendations based onhis/her past eating habits and current health conditions. When the usergets home, a smart thermostat has heated the home to the user'spreferred temperature and a smart TV has remembered that the user lovesto watch the evening news with CBS Dan Rather after work.

Furthermore, the usefulness of a personal web can be enhanced byconnecting it with sensors, wherein the sensors are also connected withthe internet and the portable internet appliance 1600.

The user has multiple passwords, identifications, services and devices.But security across them is fragmented. A digital security protector(DSP) will sort through contextual, situational and historical data toverify the user's identity on different devices including the user'sidentity with biometric data in near real-time/real-time. The digitalsecurity protector can learn about the user's social graph (as describedin FIG. 25) and make an inference about the user behavior that is out ofthe norm or may be due to someone stealing that user's identity. Basedon the user's social graph, the digital security protector will know theuser intimately, for example if a particular user is a vegetarian, butsomeone is buying a non-vegetarian food with the user's credit card, thedigital security protector will automatically close the credit card inquestion. Thus, the online security is based on intimacy with the user'ssocial graph; rather than a collection of various fragmented passwords.

Furthermore, the one integrated user identification can be embedded withhis/her digital security protector.

FIG. 25 illustrates a social graph of a user, enabled by (a) sensors(e.g., a location determination module-indoor positioning system/globalpositioning system), (b) individual data patterns of the user, (c) analgorithm for generating the user's social graph with machinetransformations, wherein the algorithm for generating the compositesocial graph with machine transformations can be stored in a local datastorage unit of the portable internet appliance 1600 or a cloud baseddata storage unit and (d) mathematical/statistical algorithm of Big Datastored in a cloud based data storage.

Near real-time/real-time snapshots/holographic snapshots (e.g.,images/videos) of the contextual world around the user can be colorenhanced/edited/geotagged/personalized (e.g., personalized withemoji/emoticon) by utilizing an algorithm(s). The user's (or the user'sone integrated user identification) social graph and/or social geotagcan be linked with a virtual avatar.

Near real-time/real-time snapshots/holographic snapshots (e.g.,images/videos) by a camera (e.g., camera of the portable internetappliance 1600) can be instantly recognized (with/without muchinformation about the snapshots/holographic snapshots)/colorenahanced/edited/geotagaged/personalized by utilizing an algorithm(s).Furthermore, near real-time/real-time snapshots/holographic snapshotscan be integrated with the virtual avatar (and the virtual avatar can belinked with a public/consortium/private blockchain) and shared via theinternet or a cloud based data storage unit via the portable internetappliance 1600 (the portable internet appliance 1600 and/or nearreal-time/real-time wearable bioelectronics subsystem 1580, as anaugmented reality personal assistant, can be sensor-aware orcontext-aware) by utilizing an algorithm(s).

The user can store his/her social graph and/or social geotag in his/herpersonal cloud via a microcomputer (e.g., Raspberry Pi) with properlyimplemented cryptography. The user can auction/monetize his/her socialgraph with or without social geotag by utilizing an algorithm(s) or optout. The price of the user's social graph with or without social geotagcan be based on the utility function of his/her social graph and/orsocial geotag to an advertiser. Furthermore, the user can securelyhost/store his/her own files and data (which can be used at any place,any time and any device) in his/her personal cloud via a microcomputer.Such a microcomputer can enable secure communication (e.g., Bitmail) andconnect with other systems/subsystems/objects/biological objects via apersonal network (e.g., Wi-Fi). Instead of talking to a centralizede-mail mail server at Google, Bitmail can distribute messages acrossnetworks of peer users, encrypting Bitmail's address and contentautomatically. Furthermore, peer users can help store and only deliverBitmail to the intended recipient user. Bitmail can obscure the sender'sidentity and an alternate Bitmail address can send Bitmail on the user'sbehalf. Additionally, such a microcomputer can enable online payment,protecting privacy of the user via the user's virtual avatar (which canbe linked with a blockchain). Through the user's virtual avatar, theuser just would need to supply/apply a fragment of information necessaryto receive a service (e.g., purchasing an item). Furthermore,intelligence from the user's social graph and/or social geotag can berealized by an intelligent learning set of instructions, which caninclude: artificial intelligence (including self-learning artificialintelligence), computer vision (self-learning camera vision), datamining, fuzzy/neuro-fuzzy logic, machine vision (including self-learningmachine vision), natural language processing, neural networks (includingself-learning neural networks), pattern recognition, reasoning modelingand self-learning (including evidence based self-learning).

It should be noted that the set of instructions of the self-learningartificial intelligence and/or self-learning neural networks algorithmcan include a quantum computer enhanced machine learning algorithm andsuch realized intelligence can enable targeted advertisement to theuser/user's virtual avatar.

Furthermore, the user/user's virtual avatar can interact with targetedadvertisement (e.g., images/videos), based on intelligence from theuser's social graph and/or social geotag and intelligence from the userin the user interface.

FIG. 26 illustrates a flow chart linking one user with many users,utilizing machine transformations. In step 2000, an algorithm performsclustering of inputs from one integrated user identification. In step2020, the algorithm weighs inputs for importance. In step 2040, weightedinputs are identified for key words. In step 2060, key words of one userare matched with key words of another user. In step 2080, a user islinked with another user, when 70% of key words are matched. In step2100, all previous steps (from step 2000 to step 2080) are repeateduntil there is a composite linking map.

FIG. 27 illustrates patterns of various applications or functions ofmany users and analyzes such patterns by a cloud based machinelearning/deep learning neural networks based learning/relearning expertcognitive computer. Collective complex patterns of many users can beanalyzed by topological analysis for data shape/structure and predictivemodeling.

FIG. 28 illustrates a composite social graph of many users, enabled by(a) sensors (e.g., a location determination module-indoor positioningsystem/global positioning system), (b) collective data patterns, (c) analgorithm for generating the composite social graph with machinetransformations, wherein the algorithm for generating the compositesocial graph with machine transformations can be stored in a local datastorage unit of the portable internet appliance 1600 or a cloud baseddata storage unit and (d) mathematical/statistical algorithm of Big Datastored in a cloud based data storage unit.

The collective data patterns may include location, web tracking,message/e-mail, social media/message, real-time bidding/auction, onlinepurchase and online/digital banking.

FIG. 29 illustrates a method of extracting intelligence and predictionfrom the collective data patterns, utilizing machine transformations. Instep 2100, a composite linking map is produced. In step 2120, thestructure or shape of data is analyzed by topological data analysis. Instep 2140, augmented intelligence analysis is performed. In step 2160,artificial intelligence (including self-learning artificialintelligence) based analysis is performed. In step 2180, artificialneural networks (including self-learning artificial neural networks)based learning is performed. In step 2200, fuzzy logic based learning isperformed. In step 2220, artificial neuro-fuzzy logic based learning isperformed. In step 2240, predictive modeling is performed. Furthermore,step 2240, of predictive modeling is linked with the step 2160 ofartificial intelligence (including self-learning artificialintelligence) based analysis. Steps 2100 to 2240 can be realized by aseries of machine transformations in conjunction with themicroprocessor/super-processor or system-on-chip/neural networks basedsystem-on-chip. System-on-chip/neural networks based system-on-chip canreplace the microprocessor/super-processor and enable cognitive/neurallike computing.

Fuzzy logic is a form of approximate reasoning, that can representvariation or imprecision in logic by making use of a natural language inlogic. An artificial neural network can approximate a function, but itis impossible to interpret the result in terms of a natural language.Artificial neuro-fuzzy system is based on combinations of artificialneural networks and fuzzy logic.

The one integrated used identification can also enable collaboration,without needing to download any software. A user can click to join forcollaboration (with many users) on one integrated used identificationplatform.

By way of an example of an application and not by way of any limitation,utilizing steps 2120, 2140, 2160, 2180, 2200, 2220 and 2240, a targetedmarketing campaign via viral meme can be realized. Furthermore, themarketer can enhance user response to a particular advertisement, byutilizing augmented reality. In another example, a marketer cananticipate what a particular user wants and needs for a car. A marketercan ask if the user would like to see a certain model of a car and thenhave a salesperson meet the user at a place, where that model of the caris located. Thus, the shopping experience can integrate both online andoffline.

Analysis of Big Data Related to Users' Social Graphs/Personal Analytics

Big Data can be converted into a smaller data set, utilizing linearsimplification and/or signal clustering, as the underlying data hasgeometrical structures and patterns (repeated over time). Furthermore,signal clustering can be categorized and weighted for importance.Alternatively, topological data analysis or Bayesian analysis coupledwith Markov chain Monte Carlo methods can be utilized for analysis ofBig Data. Analysis of Big Data can be coupled with an augmentedintelligence modeling algorithm and/or predictive modeling algorithm.Furthermore, analysis of Big Data in an unstructured format/naturallanguage can be realized by a cloud based machine learning/deep learningneural networks based learning/relearning interactive expert cognitivecomputer. Furthermore, analysis of Big Data can be coupled with anintelligent learning set of instructions. A first intelligent learningset of instructions can include: artificial intelligence (includingself-learning artificial intelligence), computer vision (includingself-learning computer vision), data mining, fuzzy/neuro-fuzzy logic,machine vision (including self-learning machine vision), naturallanguage processing, neural networks (including self-learning neuralnetworks), pattern recognition, reasoning modeling and self-learning(including evidence based self-learning).

It should be noted that artificial intelligence (including self-learningartificial intelligence), computer vision (including self-learningcomputer vision), data mining, fuzzy/neuro-fuzzy logic, machine vision(including self-learning machine vision), natural language processing,neural networks (including self-learning neural networks), patternrecognition, reasoning modeling and self-learning (including evidencebased self-learning) can be enhanced by quantum computing or quantumcomputing based machine learning.

A second intelligent learning set of instructions can include:algorithm-as-a-service, behavior modeling, physical search algorithm andsoftware agent.

The behavior modeling can be described as-a user's behavior patterns arestored in a data storage module of the portable internet appliance 1600or in a cloud based data storage unit. A data mining algorithm and/or adata interpretation algorithm can analyze the user's behavior patterns.Furthermore, a machine learning/deep learning neural networks basedlearning/relearning software module can learn and relearn the user'sbehavior patterns to intimately identify the user.

A physical search algorithm can be utilized to search or search about aphysical item (e.g., “Google my wallet?”). A software agent can searchthe internet for a particular topic/physical item with/without a humaninput. The software agent can further recommend information about theparticular topic/physical item to the user.

Additionally, it should be noted that all components/devices and/orapplication examples and/or embodiments of the near real-time/real-timewearable bioelectronics subsystem 1580, as an augmented reality personalassistant can be utilized with the portable internet appliance 1600.

It should be apparent that one or more features of the portable internetappliance 1600 can be combined with one or more features of the nearreal-time/real-time wearable bioelectronics subsystem 1580.Additionally, the applications, as illustrated in FIGS. 21, 22A, 22B,23, 24, 25, 26, 27, 28 and 29 can be realized by the nearreal-time/real-time wearable bioelectronics subsystem 1580, as anaugmented reality personal assistant.

Interactions of Networks of Objects/Biological Objects with the PortableInternet Appliance

“Google my wallet?” would give the user the right answer, if the user'swallet is embedded with an object (an object is illustrated in FIGS.18E, 18F, 18G and 18H).

Furthermore, the object can be fabricated/constructed, as nanostructuredmesh (as described in Table-16A and Table-16B), wherein eachnanostructured mesh can be integrated with other suitable circuits andsensors.

TABLE 16A Compositions For A Nanostructured Mesh For An Object Com Wt %Wt % Wt % Wt % positions Material A Material B Material C Material D 180% Hydrogel 20% Chitin 2 80% Hydrogel 20% Chitosan 3 80% Hydrogel 20%Fibroin 4 80% Hydrogel 10% Chitin 10% Chitosan 5 80% Hydrogel 10% Chitin10% Fibroin 6 80% Hydrogel 10% Chitosan 10% Fibroin 7 80% Hydrogel 10%Chitin 10% PGLA 8 80% Hydrogel 10% Chitosan 10% PGLA 9 80% Hydrogel 10%Fibroin 10% PGLA 10 70% Hydrogel 10% Chitin 10% Fibroin 10% PGLA 11 70%Hydrogel 10% Chitosan 10% Fibroin 10% PGLA

TABLE 16B Nanostructured Mesh (For An Object) Integrated With VariousNanowire Field Effect Transistors Com- positions From Integrated With AnArray Table-16A Of Nanowire Field Effect Transistors 1Nanowire^(P1)/Nanowire^(P2)/Nanowire^(P3)/Nanowire^(z)/Nanowire^(c) 2Nanowire^(P1)/Nanowire^(P2)/Nanowire^(P3)/Nanowire^(z)/Nanowire^(c) 3Nanowire^(P1)/Nanowire^(P2)/Nanowire^(P3)/Nanowire^(z)/Nanowire^(c) 4Nanowire^(P1)/Nanowire^(P2)/Nanowire^(P3)/Nanowire^(z)/Nanowire^(c) 5Nanowire^(P1)/Nanowire^(P2)/Nanowire^(P3)/Nanowire^(z)/Nanowire^(c) 6Nanowire^(P1)/Nanowire^(P2)/Nanowire^(P3)/Nanowire^(z)/Nanowire^(c) 7Nanowire^(P1)/Nanowire^(P2)/Nanowire^(P3)/Nanowire^(z)/Nanowire^(c) 8Nanowire^(P1)/Nanowire^(P2)/Nanowire^(P3)/Nanowire^(z)/Nanowire^(c) 9Nanowire^(P1)/Nanowire^(P2)/Nanowire^(P3)/Nanowire^(z)/Nanowire^(c) 10Nanowire^(P1)/Nanowire^(P2)/Nanowire^(P3)/Nanowire^(z)/Nanowire^(c) 11Nanowire^(P1)/Nanowire^(P2)/Nanowire^(P3)/Nanowire^(z)/Nanowire^(c)

Nanowire^(P1) field effect transistor is a polymer nanowire field effecttransistor (optionally coated with a lipid layer).

Nanowire^(P2) field effect transistor is an engineered protein nanowirefield effect transistor (optionally coated with a lipid layer). Anengineered protein based field effect transistor can befabricated/constructed, utilizing a suitable material decorated onengineered protein (e.g., a three-dimensional ball and spike engineeredprotein-synthesized by a fusion of both Dps and gp5c genes).

Nanowire^(P3) field effect transistor is a proton nanowire field effecttransistor (optionally coated with a lipid layer). A natural biopolymerchitosan/melanin based proton field effect transistor, whichincorporates a polymer substrate as a gate, a gate oxide insulator film,a source metal thin-film and a drain metal thin-film for proton current.

Nanowire^(z) field effect transistor is a zinc oxide wire nanowire fieldeffect transistor (optionally coated with a lipid layer).

Nanowire^(C) field effect transistor is a carbon nanotube nanofiberfield effect transistor (optionally coated with a lipid layer).

Similarly, a biological object can be fabricated/constructed, utilizinga nanostructured mesh (as described in Table-16A and Table-16B)integrated with suitable biocompatible circuits and biosensors. Abiological object can be fabricated/constructed as biodissolvable,utilizing electronic circuits based on silicon nanowires and/or silknanowires.

Furthermore, an object/biological object can be decorated/tagged with anano-scaled label (an array of quantum dots or semiconductornanocrystals) to absorb and emit light at a specific wavelength foridentification. The nano-scaled label can be suitably excited by aninvisible ultraviolet (UV) laser from a distance and detected by aninfrared camera from a distance.

Furthermore, an object/biological can be integrated with amicroelectro-mechanical-system-piezoelectric based actuator for movementor a propeller. Networks of objects/biological objects can be utilizedfor recording and/or transmitting audio-visual information in asituation (e.g., a battlefield).

Networks of objects/biological objects (wherein each object/biologicalobject is integrated with microelectro-mechanical-system-piezoelectricbased actuator) can be utilized as collective assassins (wherein anano-scaled reservoir within an object/biological object is filled atoxic chemical) in a battlefield.

All the algorithms and/or software programs and/or software applicationprograms (“apps”) in the above disclosed specifications reside in acomputer system, wherein the computer system generally can include: apremise based computer system and/or a cloud based computer and/or acloud based machine learning/deep learning neural networks basedlearning/relearning interactive expert cognitive computer system,wherein the computer system can include: one or more hardware (e.g.,microprocessors/super-processors) in communication with a computerreadable medium storing one or more algorithms and/or software programsand/or software application programs (“apps”) including instructionsthat are executable by the one or more hardware (e.g.,microprocessors/super-processors).

In the above disclosed specifications “/” has been used to indicate an“or” and real-time means near real-time in practice.

The word “unit” is synonymous with the word “media unit” or with theword “media”. A cloud based storage unit is synonymous with a cloudbased server.

PREFERRED EMBODIMENTS & SCOPE OF THE INVENTION

Any example in the above disclosed specifications is by way of anexample only and not by way of any limitation.

The best mode requirement “requires an inventor(s) to disclose the bestmode contemplated by him/her, as of the time he/she executes theapplication, of carrying out the invention.” “ . . . [T]he existence ofa best mode is a purely subjective matter depending upon what theinventor(s) actually believed at the time the application was filed.”See Bayer AG v. Schein Pharmaceuticals, Inc. The best mode requirementstill exists under the America Invents Act (AIA). At the time of theinvention, the inventor(s) described preferred best mode embodiments ofthe present invention. The sole purpose of the best mode requirement isto restrain the inventor(s) from applying for a patent, while at thesame time concealing from the public preferred embodiments of theirinventions, which they have in fact conceived. The best mode inquiryfocuses on the inventor(s)' state of mind at the time he/she filed thepatent application, raising a subjective factual question. Thespecificity of disclosure required to comply with the best moderequirement must be determined by the knowledge of facts within thepossession of the inventor(s) at the time of filing the patentapplication. See Glaxo, Inc. v. Novopharm LTD., 52 F.3d 1043, 1050 (Fed.Cir. 1995).

The above disclosed specifications are the preferred best modeembodiments of the present invention. However, they are not intended tobe limited only to the preferred best mode embodiments of the presentinvention. Numerous variations and/or modifications are possible withinthe scope of the present invention. Accordingly, the disclosed preferredbest mode embodiments are to be construed as illustrative only. Thosewho are skilled in the art can make various variations and/ormodifications (e.g., a light emitting diode instead of a laser, orelectrically/wirelessly coupled instead of electrically/wirelesslyconnected, or a cloud based storage unit instead of a cloud basedserver, whenever it is applicable) without departing from the scope andspirit of this invention. It should be apparent that features of oneembodiment can be combined with one or more features of anotherembodiment to form a plurality of embodiments. The inventor(s) of thepresent invention is not required to describe each and every conceivableand possible future embodiment in the preferred best mode embodiments ofthe present invention. See SRI Int'l v. Matsushita Elec. Corp. ofAmerica, 775F.2d 1107, 1121, 227 U.S.P.Q. (BNA) 577, 585 (Fed. Cir.1985) (enbanc).

The scope and spirit of this invention shall be defined by the claimsand the equivalents of the claims only. The exclusive use of allvariations and/or modifications within the scope of the claims isreserved. The general presumption is that claim terms should beinterpreted using their plain and ordinary meaning. See Oxford ImmunotecLtd. v. Qiagen, Inc. et al., Action No. 15-cv-13124-NMG. Unless a claimterm is specifically defined in the preferred best mode embodiments,then a claim term has an ordinary meaning, as understood by a personwith an ordinary skill in the art, at the time of the present invention.As noted long ago: “Specifications teach. Claims claim”. See RexnordCorp. v. Laitram Corp., 274 F.3d 1336, 1344 (Fed. Cir. 2001). The rightsof claims (and rights of the equivalents of the claims) under theDoctrine of Equivalents-meeting the “Triple Identity Test” (a)performing substantially the same function, (b) in substantially thesame way and (c) yielding substantially the same result. See CrownPackaging Tech., Inc. v. Rexam Beverage Can Co., 559 F.3d 1308, 1312(Fed. Cir. 2009)) of the present invention are not narrowed or limitedby the selective imports of the specifications (of the preferredembodiments of the present invention) into the claims.

The term “means” was not used nor intended nor implied in the disclosedpreferred best mode embodiments of the present invention. Thus, theinventor(s) has not limited the scope of the claims as mean plusfunction. Additionally, “apparatus claims are not necessarily indefinitefor using functional language . . . [f]unctional language may also beemployed to limit the claims without using the means-plus-functionformat.” See Microprocessor Enhancement Corp. v. Texas Instruments Inc.

I claim:
 1. An optical biomodule comprises: (a) a fluidic container;wherein a substrate of the fluidic container comprises: one or morematerials, wherein the fluidic container comprises: a first biomarkerbinder or a second biomarker binder, wherein the first biomarker binderis coupled with a first fluorophore or a first photoswitchablefluorophore, wherein the fluidic container comprises: one or morethree-dimensional (3-D) protruded structures, wherein the firstfluorophore or the first photoswitchable fluorophore is positionedhorizontally relative to an open space of the one three-dimensional(3-D) protruded structure or the second biomarker binder is positionedhorizontally relative to the open space of the one three-dimensional(3-D) protruded structure, wherein a dimension or shape of the onethree-dimensional (3-D) protruded structure is varied for maximumenhancement of fluorescence emission, wherein more than the onethree-dimensional (3-D) protruded structures are spaced or arranged in aone-dimensional (1-D) array or in a two-dimensional (2-D) array, whereina pitch or a gap or a duty cycle of the one-dimensional (1-D) array orthe two-dimensional (2-D) array of the three-dimensional (3-D) protrudedstructures is varied for maximum enhancement of the fluorescenceemission; (b) a light source or light sources directed at the fluidiccontainer for inducing the fluorescence emission due to an interactionof the first biomarker binder or the second biomarker binder with abiomarker; and (c) a device for detecting the fluorescence emission fromthe fluidic container.
 2. The optical biomodule according to claim 1,wherein the substrate of the fluidic container comprises: a periodiclayers of one or more materials.
 3. The optical biomodule according toclaim 1, wherein the first biomarker binder is selected from the groupconsisting of: an isolated antibody, a synthetically designed antibody,an aptamer, a wavelength-shifting aptamer and a synthetically designedprotein, wherein the synthetically designed protein has a binding siteto bind with the biomarker.
 4. The optical biomodule according to claim1, wherein the first biomarker binder is a nano-scaled syntheticallydesigned biomolecular circuit, wherein the nano-scaled syntheticallydesigned biomolecular circuit comprises: (i) a synthetically designedriboswitch or (ii) a DNA sequence of adenine (A), thymine (T), guanine(G) and cytosine (C) or (iii) a DNA sequence of adenine (A), thymine(T), guanine, (G) cytosine (C) and a synthetically designed molecule or(iv) an RNA sequence or (v) a programmable synthetically designedDNA-targeting-cleaving enzyme or (vi) a programmable syntheticallydesigned RNA-targeting-cleaving enzyme.
 5. The optical biomoduleaccording to claim 4, wherein the nano-scaled synthetically designedbiomolecular circuit further comprises: a synthetically designedbiological logic circuit.
 6. The optical biomodule according to claim 1,wherein the first biomarker binder comprises: a nanoshell, wherein thenanoshell is decorated with a cleavable biological material, wherein thecleavable biological material is cleaved from a diseased cell or adecorated diseased cell.
 7. The optical biomodule according to claim 1,wherein the first biomarker binder comprises: a synthetically designedexosome-specific biomarker binder to couple with a molecule of anexosome.
 8. The optical biomodule according to claim 1, wherein thesecond biomarker binder comprises: an aptamer beacon or a molecularbeacon or a noble metal atom nanocluster beacon or a syntheticallydesigned riboswitch beacon.
 9. The optical biomodule according to claim8, wherein the aptamer beacon or the molecular beacon or the noble metalatom nanocluster beacon or the synthetically designed riboswitch beaconcomprises: a synthetically designed biological logic circuit.
 10. Theoptical biomodule according to claim 1, wherein the second biomarkerbinder is coupled with a nanostructural element or the second biomarkerbinder is coupled with a point defect of the nanostructural element. 11.The optical biomodule according to claim 10, wherein the nanostructuralelement is electrically conducting, wherein the nanostructural elementis electrically activated or electrically coupled with a field effecttransistor.
 12. The optical biomodule according to claim 1, wherein thesecond biomarker binder comprises: an aptamer sensor, wherein theaptamer sensor comprises: a first chemical segment to couple with thebiomarker and a second chemical segment to couple with a secondfluorophore or a second photoswitchable fluorophore.
 13. The opticalbiomodule according to claim 1, wherein the second biomarker bindercomprises: a first isolated antibody and a second isolated antibody,wherein the first isolated antibody or the second isolated antibody iscoupled with a second fluorophore or a second photoswitchablefluorophore.
 14. The optical biomodule according to claim 1, wherein thesecond biomarker binder comprises: a first synthetically designedantibody and a second synthetically designed antibody, wherein the firstsynthetically designed antibody or the second synthetically designedantibody is coupled with a second fluorophore or a secondphotoswitchable fluorophore.
 15. The optical biomodule according toclaim 14, wherein the first synthetically designed antibody or thesecond synthetically designed antibody is arranged in three-dimension(3-D).
 16. The optical biomodule according to claim 1, wherein the onethree-dimensional (3-D) protruded structure is an optical nanoantenna ora three-dimensional (3-D) protruded structure of a two-dimensional (2-D)material or a conducting nanotube or a sharp tip or a hyperbolicmetamaterial surface.
 17. The optical biomodule according to claim 16,wherein the optical nanoantenna comprises: a room temperature stabletopological insulator or a two-dimensional (2-D) material or ananoparticle.
 18. The optical biomodule according to claim 16, whereinthe hyperbolic metamaterial surface comprises: nanoholes or gratings.19. The optical biomodule according to claim 1, wherein the light sourceof the particular wavelength or the light sources of the distinctwavelengths comprises: a two-dimensional (2-D) material.
 20. The opticalbiomodule according to claim 1, wherein the light sources comprise: afirst coherent light source and a second coherent light source, whereina beam of the first coherent light source is approximately an opentoroidal shaped, wherein the first coherent light source and the secondcoherent light source are activated simultaneously.
 21. The opticalbiomodule according to claim 1, comprises: an abruptly constricted fluidcontainer, wherein a maximum dimension of the abruptly constricted fluidcontainer is less than a maximum dimension of a cell or a stem cell or aT cell.
 22. The optical biomodule according to claim 1, comprises: adevice to isolate exosomes from a biological fluid and to isolatemolecules from the exosomes, wherein the device comprises: a separatormodule to isolate exosomes-attached magnetic beads or a nano-scaledfilter to filter the exosome from the biological fluid.
 23. An opticalbiomodule comprises: (a) a fluidic container; wherein a substrate of thefluidic container comprises: one or more materials, wherein the fluidiccontainer comprises: a first biomarker binder or a second biomarkerbinder, wherein the first biomarker binder is coupled with a firstfluorophore or a first photoswitchable fluorophore, wherein the fluidiccontainer comprises: one or more three-dimensional (3-D) protrudedstructures, wherein the first fluorophore or the first photoswitchablefluorophore is positioned at about 25 nanometers or less than 25nanometers horizontally relative to the one three-dimensional (3-D)protruded structure or the second biomarker binder is positioned atabout 25 nanometers or less than 25 nanometers horizontally relative tothe one three-dimensional (3-D) protruded structure, wherein a dimensionor shape of the one three-dimensional (3-D) protruded structure isvaried for maximum enhancement of fluorescence emission, wherein morethan the one three-dimensional (3-D) protruded structures are spaced orarranged in a one-dimensional (1-D) array or in a two-dimensional (2-D)array, wherein a pitch or a gap or a duty cycle of the one-dimensional(1-D) array or the two-dimensional (2-D) array of the three-dimensional(3-D) protruded structures is varied for maximum enhancement of thefluorescence emission; (b) a light source or light sources directed atthe fluidic container for inducing the fluorescence emission due to aninteraction of the first biomarker binder or the second biomarker binderwith a biomarker; and (c) a device for detecting the fluorescenceemission from the fluidic container.
 24. An optical biomodule to detectfluorescence emission comprises: (a) a zero-mode waveguide; wherein thezero-mode waveguide comprises: one or more side walls, wherein thezero-mode waveguide comprises: a bottom base, wherein a substrate of thezero-mode waveguide consists of one or more materials, wherein thezero-mode waveguide contains or comprises: one or more biomarker bindersor immobilized single DNA polymerase molecules, wherein the zero-modewaveguide comprises: one three-dimensional (3-D) protruded structure,(b) a light source or light sources directed at the zero-mode waveguidefor inducing the fluorescence emission due to an interaction of the onebiomarker binder with a biomarker or the one immobilized single DNApolymerase molecule with a freely moving DNA-interacting protein or afreely moving phospholinked nucleotide; and (c) a device for detectingthe fluorescence emission from the zero-mode waveguide.
 25. The opticalbiomodule according to claim 24, wherein the zero-mode waveguide isfunctionalized (a) on the one side walls of the zero-mode waveguide witha monolayer of first molecules or (b) at or near the bottom base of thezero-mode waveguide with a monolayer of second molecules or (c) at ornear the bottom base of the zero-mode waveguide with a monolayer ofthird molecules to bind the one biomarker binder or the one immobilizedsingle DNA polymerase molecule.